2023
Lokki, A Inkeri | Ren, Zhen | Triebwasser, Michael | Daly, Emma | | Perola, Markus | Auro, Kirsi | Burwick, Richard | Salmon, Jane E | Daly, Mark | Laivuori, Hannele | Atkinson, John P | Java, Anuja | Meri, Seppo
Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study Journal Article
In: BJOG, vol. 130, no. 12, pp. 1473–1482, 2023, ISSN: 1471-0528.
Abstract | Links | BibTeX | Tags:
@article{pmid37156755,
title = {Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study},
author = {A Inkeri Lokki and Zhen Ren and Michael Triebwasser and Emma Daly and and Markus Perola and Kirsi Auro and Richard Burwick and Jane E Salmon and Mark Daly and Hannele Laivuori and John P Atkinson and Anuja Java and Seppo Meri},
doi = {10.1111/1471-0528.17529},
issn = {1471-0528},
year = {2023},
date = {2023-11-01},
journal = {BJOG},
volume = {130},
number = {12},
pages = {1473--1482},
abstract = {OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.nnDESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.nnSETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.nnPOPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.nnMETHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.nnMAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.nnRESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.nnCONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.nnDESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.nnSETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.nnPOPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.nnMETHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.nnMAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.nnRESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.nnCONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.
Durkin, Jaclyn | Poe, Amy R | Belfer, Samuel J | Rodriguez, Anyara | Tang, Si Hao | Walker, James A | Kayser, Matthew S
regulates early developmental sleep in Journal Article
In: Neurobiol Sleep Circadian Rhythms, vol. 15, pp. 100101, 2023, ISSN: 2451-9944.
Abstract | Links | BibTeX | Tags:
@article{pmid37593040,
title = { regulates early developmental sleep in },
author = {Jaclyn Durkin and Amy R Poe and Samuel J Belfer and Anyara Rodriguez and Si Hao Tang and James A Walker and Matthew S Kayser},
doi = {10.1016/j.nbscr.2023.100101},
issn = {2451-9944},
year = {2023},
date = {2023-11-01},
journal = {Neurobiol Sleep Circadian Rhythms},
volume = {15},
pages = {100101},
abstract = {Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including , suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene () in sleep during numerous developmental periods. Mutations in () are associated with sleep and circadian disorders in humans and adult flies. We find in flies that acts to regulate sleep across the lifespan, beginning during larval stages. is required in neurons for this function, as is signaling via the Alk pathway. These findings identify as one of a small number of genes positioned to regulate sleep across developmental periods.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including , suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene () in sleep during numerous developmental periods. Mutations in () are associated with sleep and circadian disorders in humans and adult flies. We find in flies that acts to regulate sleep across the lifespan, beginning during larval stages. is required in neurons for this function, as is signaling via the Alk pathway. These findings identify as one of a small number of genes positioned to regulate sleep across developmental periods.
McConkie-Rosell, Allyn | Spillmann, Rebecca C | Schoch, Kelly | Sullivan, Jennifer A | Walley, Nicole | McDonald, Marie | | Hooper, Stephen R | Shashi, Vandana
Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors Journal Article
In: J Genet Couns, vol. 32, no. 5, pp. 993–1008, 2023, ISSN: 1573-3599.
Abstract | Links | BibTeX | Tags:
@article{pmid37005744,
title = {Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors},
author = {Allyn McConkie-Rosell and Rebecca C Spillmann and Kelly Schoch and Jennifer A Sullivan and Nicole Walley and Marie McDonald and and Stephen R Hooper and Vandana Shashi},
doi = {10.1002/jgc4.1707},
issn = {1573-3599},
year = {2023},
date = {2023-10-01},
journal = {J Genet Couns},
volume = {32},
number = {5},
pages = {993--1008},
abstract = {Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors-genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining participation in the study. Exploratory analyses revealed multiple co-occurring practical barriers, greater emotional exhaustion and research hesitancy in the parents in the Decliner group compared to the Participants, with both groups identifying a similar number of facilitators. The parents in the Decliner group also had lower genomic knowledge, but distrust of clinical research was not different between the groups. Importantly, despite their non-participation, those in the Decliner group indicated an interest in obtaining a diagnosis and expressed confidence in being able to emotionally manage the ensuing results. Study findings support the concept that some families who decline participation in diagnostic genomic research may be experiencing pile-up with exhaustion of family resources - making participation in the genomic research difficult. This study highlights the complexity of the factors that underlie non-participation in clinically relevant NGS research. Thus, approaches to mitigating barriers to NGS research participation by populations experiencing health disparities need to be multi-pronged and tailored so that they can benefit from state-of -the art genomic technologies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors-genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining participation in the study. Exploratory analyses revealed multiple co-occurring practical barriers, greater emotional exhaustion and research hesitancy in the parents in the Decliner group compared to the Participants, with both groups identifying a similar number of facilitators. The parents in the Decliner group also had lower genomic knowledge, but distrust of clinical research was not different between the groups. Importantly, despite their non-participation, those in the Decliner group indicated an interest in obtaining a diagnosis and expressed confidence in being able to emotionally manage the ensuing results. Study findings support the concept that some families who decline participation in diagnostic genomic research may be experiencing pile-up with exhaustion of family resources - making participation in the genomic research difficult. This study highlights the complexity of the factors that underlie non-participation in clinically relevant NGS research. Thus, approaches to mitigating barriers to NGS research participation by populations experiencing health disparities need to be multi-pronged and tailored so that they can benefit from state-of -the art genomic technologies.
Perlis, Roy H | Fihn, Stephan D
Evaluating the Application of Large Language Models in Clinical Research Contexts Journal Article
In: JAMA Netw Open, vol. 6, no. 10, pp. e2335924, 2023, ISSN: 2574-3805.
@article{pmid37782501,
title = {Evaluating the Application of Large Language Models in Clinical Research Contexts},
author = {Roy H Perlis and Stephan D Fihn},
doi = {10.1001/jamanetworkopen.2023.35924},
issn = {2574-3805},
year = {2023},
date = {2023-10-01},
journal = {JAMA Netw Open},
volume = {6},
number = {10},
pages = {e2335924},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Rahmoune, Adline | Winkler, Marion F | Saxena, Richa | Compher, Charlene | Dashti, Hassan S
In: Nutr Clin Pract, 2023, ISSN: 1941-2452.
Abstract | Links | BibTeX | Tags:
@article{pmid37777983,
title = {Comparison between self-reported and actigraphy-derived sleep measures in patients receiving home parenteral nutrition: Secondary analysis of observational data},
author = {Adline Rahmoune and Marion F Winkler and Richa Saxena and Charlene Compher and Hassan S Dashti},
doi = {10.1002/ncp.11077},
issn = {1941-2452},
year = {2023},
date = {2023-10-01},
journal = {Nutr Clin Pract},
abstract = {BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN.nnMETHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement.nnRESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL.nnCONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN.nnMETHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement.nnRESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL.nnCONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.
Mazurek, Mercy H | Parasuram, Nethra R | Peng, Teng J | Beekman, Rachel | Yadlapalli, Vineetha | Sorby-Adams, Annabel J | Lalwani, Dheeraj | Zabinska, Julia | Gilmore, Emily J | Petersen, Nils H | Falcone, Guido J | Sujijantarat, Nanthiya | Matouk, Charles | Payabvash, Sam | Sze, Gordon | Schiff, Steven J | Iglesias, Juan Eugenio | Rosen, Matthew S | de Havenon, Adam | Kimberly, W Taylor | Sheth, Kevin N
Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke Journal Article
In: Stroke, 2023, ISSN: 1524-4628.
Abstract | Links | BibTeX | Tags:
@article{pmid37795593,
title = {Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke},
author = {Mercy H Mazurek and Nethra R Parasuram and Teng J Peng and Rachel Beekman and Vineetha Yadlapalli and Annabel J Sorby-Adams and Dheeraj Lalwani and Julia Zabinska and Emily J Gilmore and Nils H Petersen and Guido J Falcone and Nanthiya Sujijantarat and Charles Matouk and Sam Payabvash and Gordon Sze and Steven J Schiff and Juan Eugenio Iglesias and Matthew S Rosen and Adam de Havenon and W Taylor Kimberly and Kevin N Sheth},
doi = {10.1161/STROKEAHA.123.043146},
issn = {1524-4628},
year = {2023},
date = {2023-10-01},
journal = {Stroke},
abstract = {BACKGROUND: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection.nnMETHODS: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances.nnRESULTS: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively.nnCONCLUSIONS: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection.nnMETHODS: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances.nnRESULTS: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively.nnCONCLUSIONS: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH.
Parodi, Livia | Comeau, Mary E | Georgakis, Marios K | Mayerhofer, Ernst | Chung, Jaeyoon | Falcone, Guido J | Malik, Rainer | Demel, Stacie L | Worrall, Bradford B | Koch, Sebastian | Testai, Fernando D | Kittner, Steven J | McCauley, Jacob L | Hall, Christiana E | Mayson, Douglas J | Elkind, Mitchell Sv | James, Michael L | Woo, Daniel | Rosand, Jonathan | Langefeld, Carl D | Anderson, Christopher D
Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage Journal Article
In: Ann Neurol, 2023, ISSN: 1531-8249.
Abstract | Links | BibTeX | Tags:
@article{pmid37787451,
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage},
author = {Livia Parodi and Mary E Comeau and Marios K Georgakis and Ernst Mayerhofer and Jaeyoon Chung and Guido J Falcone and Rainer Malik and Stacie L Demel and Bradford B Worrall and Sebastian Koch and Fernando D Testai and Steven J Kittner and Jacob L McCauley and Christiana E Hall and Douglas J Mayson and Mitchell Sv Elkind and Michael L James and Daniel Woo and Jonathan Rosand and Carl D Langefeld and Christopher D Anderson},
doi = {10.1002/ana.26814},
issn = {1531-8249},
year = {2023},
date = {2023-10-01},
journal = {Ann Neurol},
abstract = {OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.nnMETHODS: 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44 and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.nnRESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.nnINTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and CSVD. This article is protected by copyright. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.nnMETHODS: 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44 and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.nnRESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.nnINTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and CSVD. This article is protected by copyright. All rights reserved.
Misra, Shivani | Wagner, Robert | Ozkan, Bige | Schön, Martin | Sevilla-Gonzalez, Magdalena | Prystupa, Katsiaryna | Wang, Caroline C | Kreienkamp, Raymond J | Cromer, Sara J | Rooney, Mary R | Duan, Daisy | Thuesen, Anne Cathrine Baun | Wallace, Amelia S | Leong, Aaron | Deutsch, Aaron J | Andersen, Mette K | Billings, Liana K | Eckel, Robert H | Sheu, Wayne Huey-Herng | Hansen, Torben | Stefan, Norbert | Goodarzi, Mark O | Ray, Debashree | Selvin, Elizabeth | Florez, Jose C | | Meigs, James B | Udler, Miriam S
Precision subclassification of type 2 diabetes: a systematic review Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 138, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37798471,
title = {Precision subclassification of type 2 diabetes: a systematic review},
author = {Shivani Misra and Robert Wagner and Bige Ozkan and Martin Schön and Magdalena Sevilla-Gonzalez and Katsiaryna Prystupa and Caroline C Wang and Raymond J Kreienkamp and Sara J Cromer and Mary R Rooney and Daisy Duan and Anne Cathrine Baun Thuesen and Amelia S Wallace and Aaron Leong and Aaron J Deutsch and Mette K Andersen and Liana K Billings and Robert H Eckel and Wayne Huey-Herng Sheu and Torben Hansen and Norbert Stefan and Mark O Goodarzi and Debashree Ray and Elizabeth Selvin and Jose C Florez and and James B Meigs and Miriam S Udler},
doi = {10.1038/s43856-023-00360-3},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {138},
abstract = {BACKGROUND: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.nnMETHODS: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.nnRESULTS: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.nnCONCLUSION: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.nnMETHODS: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.nnRESULTS: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.nnCONCLUSION: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.
Felton, Jamie L | Griffin, Kurt J | Oram, Richard A | Speake, Cate | Long, S Alice | Onengut-Gumuscu, Suna | Rich, Stephen S | Monaco, Gabriela S F | Evans-Molina, Carmella | DiMeglio, Linda A | Ismail, Heba M | Steck, Andrea K | Dabelea, Dana | Johnson, Randi K | Urazbayeva, Marzhan | Gitelman, Stephen | Wentworth, John M | Redondo, Maria J | and, Emily K Sims
Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 130, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794169,
title = {Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review},
author = {Jamie L Felton and Kurt J Griffin and Richard A Oram and Cate Speake and S Alice Long and Suna Onengut-Gumuscu and Stephen S Rich and Gabriela S F Monaco and Carmella Evans-Molina and Linda A DiMeglio and Heba M Ismail and Andrea K Steck and Dana Dabelea and Randi K Johnson and Marzhan Urazbayeva and Stephen Gitelman and John M Wentworth and Maria J Redondo and Emily K Sims and },
doi = {10.1038/s43856-023-00357-y},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {130},
abstract = {BACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.nnMETHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.nnRESULTS: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings.nnCONCLUSIONS: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.nnMETHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.nnRESULTS: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings.nnCONCLUSIONS: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.
Young, Katherine G | McInnes, Eram Haider | Massey, Robert J | Kahkoska, Anna R | Pilla, Scott J | Raghavan, Sridharan | Stanislawski, Maggie A | Tobias, Deirdre K | McGovern, Andrew P | Dawed, Adem Y | Jones, Angus G | Pearson, Ewan R | and, John M Dennis
Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 131, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794166,
title = {Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review},
author = {Katherine G Young and Eram Haider McInnes and Robert J Massey and Anna R Kahkoska and Scott J Pilla and Sridharan Raghavan and Maggie A Stanislawski and Deirdre K Tobias and Andrew P McGovern and Adem Y Dawed and Angus G Jones and Ewan R Pearson and John M Dennis and },
doi = {10.1038/s43856-023-00359-w},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {131},
abstract = {BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.nnMETHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.nnRESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.nnCONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.nnMETHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.nnRESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.nnCONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.
Baumdick, Martin E | Niehrs, Annika | Degenhardt, Frauke | Schwerk, Maria | Hinrichs, Ole | Jordan-Paiz, Ana | Padoan, Benedetta | Wegner, Lucy H M | Schloer, Sebastian | Zecher, Britta F | Malsy, Jakob | Joshi, Vinita R | Illig, Christin | Schröder-Schwarz, Jennifer | Möller, Kimberly J | | Martin, Maureen P | Yuki, Yuko | Ozawa, Mikki | Sauter, Jürgen | Schmidt, Alexander H | Perez, Daniel | Giannou, Anastasios D | Carrington, Mary | Davis, Randall S | Schumacher, Udo | Sauter, Guido | Huber, Samuel | Puelles, Victor G | Melling, Nathaniel | Franke, Andre | | Altfeld, Marcus | Bunders, Madeleine J
HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44 Natural Killer Cells in Ulcerative Colitis Journal Article
In: Gastroenterology, vol. 165, no. 4, pp. 946–962.e13, 2023, ISSN: 1528-0012.
Abstract | Links | BibTeX | Tags:
@article{pmid37454979,
title = {HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44 Natural Killer Cells in Ulcerative Colitis},
author = {Martin E Baumdick and Annika Niehrs and Frauke Degenhardt and Maria Schwerk and Ole Hinrichs and Ana Jordan-Paiz and Benedetta Padoan and Lucy H M Wegner and Sebastian Schloer and Britta F Zecher and Jakob Malsy and Vinita R Joshi and Christin Illig and Jennifer Schröder-Schwarz and Kimberly J Möller and and Maureen P Martin and Yuko Yuki and Mikki Ozawa and Jürgen Sauter and Alexander H Schmidt and Daniel Perez and Anastasios D Giannou and Mary Carrington and Randall S Davis and Udo Schumacher and Guido Sauter and Samuel Huber and Victor G Puelles and Nathaniel Melling and Andre Franke and and Marcus Altfeld and Madeleine J Bunders},
doi = {10.1053/j.gastro.2023.06.034},
issn = {1528-0012},
year = {2023},
date = {2023-10-01},
journal = {Gastroenterology},
volume = {165},
number = {4},
pages = {946--962.e13},
abstract = {BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.nnMETHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.nnRESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401 individuals showed significantly stronger binding of NKp44 compared with HLA-DP301 IECs. HLA-DP401 IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44 NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301 organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.nnCONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44 NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44 NK cell-mediated destruction of the intestinal epithelium in UC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.nnMETHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.nnRESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401 individuals showed significantly stronger binding of NKp44 compared with HLA-DP301 IECs. HLA-DP401 IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44 NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301 organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.nnCONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44 NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44 NK cell-mediated destruction of the intestinal epithelium in UC.
Mesaki, Kumi | Juvet, Stephen | Yeung, Jonathan | Guan, Zehong | Wilson, Gavin W | Hu, Jim | Davidson, Alan R | Kleinstiver, Benjamin P | Cypel, Marcelo | Liu, Mingyao | Keshavjee, Shaf
Immunomodulation of the donor lung with CRISPR-mediated activation of IL-10 expression Journal Article
In: J Heart Lung Transplant, vol. 42, no. 10, pp. 1363–1377, 2023, ISSN: 1557-3117.
Abstract | Links | BibTeX | Tags:
@article{pmid37315746,
title = {Immunomodulation of the donor lung with CRISPR-mediated activation of IL-10 expression},
author = {Kumi Mesaki and Stephen Juvet and Jonathan Yeung and Zehong Guan and Gavin W Wilson and Jim Hu and Alan R Davidson and Benjamin P Kleinstiver and Marcelo Cypel and Mingyao Liu and Shaf Keshavjee},
doi = {10.1016/j.healun.2023.06.001},
issn = {1557-3117},
year = {2023},
date = {2023-10-01},
journal = {J Heart Lung Transplant},
volume = {42},
number = {10},
pages = {1363--1377},
abstract = {BACKGROUND: Inflammatory injury in the donor lung remains a persistent challenge in lung transplantation that limits donor organ usage and post-transplant outcomes. Inducing immunomodulatory capacity in donor organs could address this unsolved clinical problem. We sought to apply clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) technologies to the donor lung to fine-tune immunomodulatory gene expression, exploring for the first time the therapeutic use of CRISPR-mediated transcriptional activation in the whole donor lung.nnMETHODS: We explored the feasibility of CRISPR-mediated transcriptional upregulation of interleukin 10 (IL-10), a key immunomodulatory cytokine, in vitro and in vivo. We first evaluated the potency, titratability, and multiplexibility of the gene activation in rat and human cell lines. Next, in vivo CRISPR-mediated IL-10 activation was characterized in rat lungs. Finally, the IL-10-activated donor lungs were transplanted into recipient rats to assess the feasibility in a transplant setting.nnRESULTS: The targeted transcriptional activation induced robust and titrable IL-10 upregulation in vitro. The combination of guide RNAs also facilitated multiplex gene modulation, that is, simultaneous activation of IL-10 and IL1 receptor antagonist. In vivo profiling demonstrated that adenoviral delivery of Cas9-based activators to the lung was feasible with the use of immunosuppression, which is routinely applied to organ transplant recipients. The transcriptionally modulated donor lungs retained IL-10 upregulation in isogeneic and allogeneic recipients.nnCONCLUSIONS: Our findings highlight the potential of CRISPR epigenome editing to improve lung transplant outcomes by creating a more favorable immunomodulatory environment in the donor organ, a paradigm that may be extendable to other organ transplants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Inflammatory injury in the donor lung remains a persistent challenge in lung transplantation that limits donor organ usage and post-transplant outcomes. Inducing immunomodulatory capacity in donor organs could address this unsolved clinical problem. We sought to apply clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) technologies to the donor lung to fine-tune immunomodulatory gene expression, exploring for the first time the therapeutic use of CRISPR-mediated transcriptional activation in the whole donor lung.nnMETHODS: We explored the feasibility of CRISPR-mediated transcriptional upregulation of interleukin 10 (IL-10), a key immunomodulatory cytokine, in vitro and in vivo. We first evaluated the potency, titratability, and multiplexibility of the gene activation in rat and human cell lines. Next, in vivo CRISPR-mediated IL-10 activation was characterized in rat lungs. Finally, the IL-10-activated donor lungs were transplanted into recipient rats to assess the feasibility in a transplant setting.nnRESULTS: The targeted transcriptional activation induced robust and titrable IL-10 upregulation in vitro. The combination of guide RNAs also facilitated multiplex gene modulation, that is, simultaneous activation of IL-10 and IL1 receptor antagonist. In vivo profiling demonstrated that adenoviral delivery of Cas9-based activators to the lung was feasible with the use of immunosuppression, which is routinely applied to organ transplant recipients. The transcriptionally modulated donor lungs retained IL-10 upregulation in isogeneic and allogeneic recipients.nnCONCLUSIONS: Our findings highlight the potential of CRISPR epigenome editing to improve lung transplant outcomes by creating a more favorable immunomodulatory environment in the donor organ, a paradigm that may be extendable to other organ transplants.
Zhao, Lin | Koseki, Sabrina R T | Silverstein, Rachel A | Amrani, Nadia | Peng, Christina | Kramme, Christian | Savic, Natasha | Pacesa, Martin | Rodríguez, Tomás C | Stan, Teodora | Tysinger, Emma | Hong, Lauren | Yudistyra, Vivian | Ponnapati, Manvitha R | Jacobson, Joseph M | Church, George M | Jakimo, Noah | Truant, Ray | Jinek, Martin | Kleinstiver, Benjamin P | Sontheimer, Erik J | Chatterjee, Pranam
PAM-flexible genome editing with an engineered chimeric Cas9 Journal Article
In: Nat Commun, vol. 14, no. 1, pp. 6175, 2023, ISSN: 2041-1723.
Abstract | Links | BibTeX | Tags:
@article{pmid37794046,
title = {PAM-flexible genome editing with an engineered chimeric Cas9},
author = {Lin Zhao and Sabrina R T Koseki and Rachel A Silverstein and Nadia Amrani and Christina Peng and Christian Kramme and Natasha Savic and Martin Pacesa and Tomás C Rodríguez and Teodora Stan and Emma Tysinger and Lauren Hong and Vivian Yudistyra and Manvitha R Ponnapati and Joseph M Jacobson and George M Church and Noah Jakimo and Ray Truant and Martin Jinek and Benjamin P Kleinstiver and Erik J Sontheimer and Pranam Chatterjee},
doi = {10.1038/s41467-023-41829-y},
issn = {2041-1723},
year = {2023},
date = {2023-10-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {6175},
abstract = {CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y = C or T) PAM preference, with the N-terminus of Sc + +, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse PAMs and disease-related loci for potential therapeutic applications. In total, the approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y = C or T) PAM preference, with the N-terminus of Sc + +, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse PAMs and disease-related loci for potential therapeutic applications. In total, the approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning.
Benham, Jamie L | Gingras, Véronique | McLennan, Niamh-Maire | Most, Jasper | Yamamoto, Jennifer M | Aiken, Catherine E | Ozanne, Susan E | and, Rebecca M Reynolds
Precision gestational diabetes treatment: a systematic review and meta-analyses Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 135, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794196,
title = {Precision gestational diabetes treatment: a systematic review and meta-analyses},
author = {Jamie L Benham and Véronique Gingras and Niamh-Maire McLennan and Jasper Most and Jennifer M Yamamoto and Catherine E Aiken and Susan E Ozanne and Rebecca M Reynolds and },
doi = {10.1038/s43856-023-00371-0},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {135},
abstract = {BACKGROUND: Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus.nnMETHODS: We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions.nnRESULTS: There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis.nnCONCLUSIONS: Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus.nnMETHODS: We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions.nnRESULTS: There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis.nnCONCLUSIONS: Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.
Halley, Meghan C | Young, Jennifer L | Tang, Charis | Mintz, Kevin T | Lucas-Griffin, Sawyer | Maghiro, AudreyStephannie | Ashley, Euan A | and, Holly K Tabor
Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care Journal Article
In: J Pediatr, vol. 261, pp. 113537, 2023, ISSN: 1097-6833.
Abstract | Links | BibTeX | Tags:
@article{pmid37271495,
title = {Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care},
author = {Meghan C Halley and Jennifer L Young and Charis Tang and Kevin T Mintz and Sawyer Lucas-Griffin and AudreyStephannie Maghiro and Euan A Ashley and Holly K Tabor and },
doi = {10.1016/j.jpeds.2023.113537},
issn = {1097-6833},
year = {2023},
date = {2023-10-01},
journal = {J Pediatr},
volume = {261},
pages = {113537},
abstract = {OBJECTIVE: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.nnSTUDY DESIGN: In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.nnRESULTS: Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included (1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child, (2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation, and (3) the limited clinical benefits parents ultimately experienced for their children.nnCONCLUSIONS: Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception-in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research to communicate appropriately and balance the potential burdens and benefits of study participation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.nnSTUDY DESIGN: In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.nnRESULTS: Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included (1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child, (2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation, and (3) the limited clinical benefits parents ultimately experienced for their children.nnCONCLUSIONS: Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception-in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research to communicate appropriately and balance the potential burdens and benefits of study participation.
Semple, Robert K | Patel, Kashyap A | Auh, Sungyoung | | Brown, Rebecca J
Genotype-stratified treatment for monogenic insulin resistance: a systematic review Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 134, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794082,
title = {Genotype-stratified treatment for monogenic insulin resistance: a systematic review},
author = {Robert K Semple and Kashyap A Patel and Sungyoung Auh and and Rebecca J Brown},
doi = {10.1038/s43856-023-00368-9},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {134},
abstract = {BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology.nnMETHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.nnRESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions.nnCONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology.nnMETHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.nnRESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions.nnCONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.
Jacobsen, Laura M | Sherr, Jennifer L | Considine, Elizabeth | Chen, Angela | Peeling, Sarah M | Hulsmans, Margo | Charleer, Sara | Urazbayeva, Marzhan | Tosur, Mustafa | Alamarie, Selma | Redondo, Maria J | Hood, Korey K | Gottlieb, Peter A | Gillard, Pieter | Wong, Jessie J | Hirsch, Irl B | Pratley, Richard E | Laffel, Lori M | and, Chantal Mathieu
Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 132, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794113,
title = {Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review},
author = {Laura M Jacobsen and Jennifer L Sherr and Elizabeth Considine and Angela Chen and Sarah M Peeling and Margo Hulsmans and Sara Charleer and Marzhan Urazbayeva and Mustafa Tosur and Selma Alamarie and Maria J Redondo and Korey K Hood and Peter A Gottlieb and Pieter Gillard and Jessie J Wong and Irl B Hirsch and Richard E Pratley and Lori M Laffel and Chantal Mathieu and },
doi = {10.1038/s43856-023-00358-x},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {132},
abstract = {BACKGROUND: The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care.nnMETHODS: Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years).nnRESULTS: We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact.nnCONCLUSIONS: Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care.nnMETHODS: Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years).nnRESULTS: We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact.nnCONCLUSIONS: Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes.
Giri, Anil K | Aavikko, Mervi | Wartiovaara, Linnea | Lemmetyinen, Toni | Karjalainen, Juha | Mehtonen, Juha | Palin, Kimmo | Välimäki, Niko | Tamlander, Max | Saikkonen, Riikka | Karhu, Auli | Morgunova, Ekaterina | Sun, Benjamin | Runz, Heiko | Palta, Priit | Luo, Shuang | Joensuu, Heikki | Mäkelä, Tomi P | Kostiainen, Iiro | Schalin-Jäntti, Camilla | FinnGen, | Palotie, Aarno | Aaltonen, Lauri A | Ollila, Saara | Daly, Mark J
Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5 Journal Article
In: Gastroenterology, vol. 165, no. 4, pp. 861–873, 2023, ISSN: 1528-0012.
Abstract | Links | BibTeX | Tags:
@article{pmid37453564,
title = {Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5},
author = {Anil K Giri and Mervi Aavikko and Linnea Wartiovaara and Toni Lemmetyinen and Juha Karjalainen and Juha Mehtonen and Kimmo Palin and Niko Välimäki and Max Tamlander and Riikka Saikkonen and Auli Karhu and Ekaterina Morgunova and Benjamin Sun and Heiko Runz and Priit Palta and Shuang Luo and Heikki Joensuu and Tomi P Mäkelä and Iiro Kostiainen and Camilla Schalin-Jäntti and FinnGen and Aarno Palotie and Lauri A Aaltonen and Saara Ollila and Mark J Daly},
doi = {10.1053/j.gastro.2023.06.031},
issn = {1528-0012},
year = {2023},
date = {2023-10-01},
journal = {Gastroenterology},
volume = {165},
number = {4},
pages = {861--873},
abstract = {BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.nnMETHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).nnRESULTS: We identified 6 genome-wide significant (P < 5 × 10) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.nnCONCLUSIONS: Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.nnMETHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).nnRESULTS: We identified 6 genome-wide significant (P < 5 × 10) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.nnCONCLUSIONS: Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.
Murphy, Rinki | Colclough, Kevin | Pollin, Toni I | Ikle, Jennifer M | Svalastoga, Pernille | Maloney, Kristin A | Saint-Martin, Cécile | Molnes, Janne | | Misra, Shivani | Aukrust, Ingvild | de Franco, Elisa | Flanagan, Sarah E | Njølstad, Pål R | Billings, Liana K | Owen, Katharine R | Gloyn, Anna L
The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 136, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794142,
title = {The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion},
author = {Rinki Murphy and Kevin Colclough and Toni I Pollin and Jennifer M Ikle and Pernille Svalastoga and Kristin A Maloney and Cécile Saint-Martin and Janne Molnes and and Shivani Misra and Ingvild Aukrust and Elisa de Franco and Sarah E Flanagan and Pål R Njølstad and Liana K Billings and Katharine R Owen and Anna L Gloyn},
doi = {10.1038/s43856-023-00369-8},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {136},
abstract = {BACKGROUND: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field.nnMETHODS: Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice.nnRESULTS: There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted.nnCONCLUSIONS: We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field.nnMETHODS: Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice.nnRESULTS: There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted.nnCONCLUSIONS: We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.
Robinson, Kelsey | Mosley, Trenell J | Rivera-González, Kenneth S | Jabbarpour, Christopher R | Curtis, Sarah W | Adeyemo, Wasiu Lanre | Beaty, Terri H | Butali, Azeez | Buxó, Carmen J | Cutler, David J | Epstein, Michael P | Gowans, Lord J J | Hecht, Jacqueline T | Murray, Jeffrey C | Shaw, Gary M | Uribe, Lina Moreno | Weinberg, Seth M | Brand, Harrison | Marazita, Mary L | Lipinski, Robert J | Leslie, Elizabeth J
Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate Journal Article
In: HGG Adv, vol. 4, no. 4, pp. 100234, 2023, ISSN: 2666-2477.
Abstract | Links | BibTeX | Tags:
@article{pmid37719664,
title = {Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate},
author = {Kelsey Robinson and Trenell J Mosley and Kenneth S Rivera-González and Christopher R Jabbarpour and Sarah W Curtis and Wasiu Lanre Adeyemo and Terri H Beaty and Azeez Butali and Carmen J Buxó and David J Cutler and Michael P Epstein and Lord J J Gowans and Jacqueline T Hecht and Jeffrey C Murray and Gary M Shaw and Lina Moreno Uribe and Seth M Weinberg and Harrison Brand and Mary L Marazita and Robert J Lipinski and Elizabeth J Leslie},
doi = {10.1016/j.xhgg.2023.100234},
issn = {2666-2477},
year = {2023},
date = {2023-10-01},
journal = {HGG Adv},
volume = {4},
number = {4},
pages = {100234},
abstract = {Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10) associated with CHP. One gene at this locus, angiopoietin-like 2 (), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10) associated with CHP. One gene at this locus, angiopoietin-like 2 (), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.
Vidal-Ribas, Pablo | Govender, Theemeshni | Yu, Jing | Sundaram, Rajeshwari | Perlis, Roy H | Gilman, Stephen E
Children's cognitive performance and suicide risk through middle adulthood Journal Article
In: J Child Psychol Psychiatry, vol. 64, no. 10, pp. 1480–1491, 2023, ISSN: 1469-7610.
Abstract | Links | BibTeX | Tags:
@article{pmid37263773,
title = {Children's cognitive performance and suicide risk through middle adulthood},
author = {Pablo Vidal-Ribas and Theemeshni Govender and Jing Yu and Rajeshwari Sundaram and Roy H Perlis and Stephen E Gilman},
doi = {10.1111/jcpp.13841},
issn = {1469-7610},
year = {2023},
date = {2023-10-01},
journal = {J Child Psychol Psychiatry},
volume = {64},
number = {10},
pages = {1480--1491},
abstract = {BACKGROUND: Longitudinal studies show that lower cognitive performance in adolescence and early adulthood is associated with higher risk of suicide death throughout adulthood. However, it is unclear whether this cognitive vulnerability originates earlier in childhood since studies conducted in children are scarce and have inconsistent results.nnMETHODS: Vital status of 49,853 individuals born between 1959 and 1966 to participants in the Collaborative Perinatal Project cohort was determined by a probabilistic linkage to the National Death Index, covering all US deaths occurring from 1979 through 2016. Cox proportional hazard models were used to examine associations of general, verbal, and non-verbal intelligence at ages 4 and 7, and academic skills at age 7 with suicide death coded according to ICD-9/10 criteria, while accounting for sociodemographic and pregnancy factors previously associated with suicide in this sample.nnRESULTS: By the end of 2016, 288 cohort members had died by suicide. Cognitive performance at 7 years on tests with verbal components was associated with suicide risk (average vs. high verbal intelligence, HR = 1.97, 95% CI 1.05-3.71; low vs. high spelling skills, HR = 2.02, 95% CI 1.16-3.51; low vs. high reading skills, HR = 2.01, 95% CI 1.27-3.17). Associations were still evident, especially for verbal intelligence and reading skills, but hazard ratios were attenuated after adjusting for prenatal and sociodemographic factors at birth (verbal intelligence, HR = 1.97, 95% CI 1.03-3.78; spelling, HR = 1.61, 95% CI 0.90-2.88; reading, HR = 1.67, 95% CI 1.02-2.72).nnCONCLUSIONS: Childhood neurocognitive performance is associated with vulnerability to suicide mortality through middle-adulthood, suggesting that there might be a cognitive diathesis for suicide originating in early childhood. Future studies should examine how multiple domains of childhood cognitive performance contribute to vulnerability to suicide risk, including by increasing risk for social and environmental factors that are associated not only with suicide but also with many types of psychiatric disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Longitudinal studies show that lower cognitive performance in adolescence and early adulthood is associated with higher risk of suicide death throughout adulthood. However, it is unclear whether this cognitive vulnerability originates earlier in childhood since studies conducted in children are scarce and have inconsistent results.nnMETHODS: Vital status of 49,853 individuals born between 1959 and 1966 to participants in the Collaborative Perinatal Project cohort was determined by a probabilistic linkage to the National Death Index, covering all US deaths occurring from 1979 through 2016. Cox proportional hazard models were used to examine associations of general, verbal, and non-verbal intelligence at ages 4 and 7, and academic skills at age 7 with suicide death coded according to ICD-9/10 criteria, while accounting for sociodemographic and pregnancy factors previously associated with suicide in this sample.nnRESULTS: By the end of 2016, 288 cohort members had died by suicide. Cognitive performance at 7 years on tests with verbal components was associated with suicide risk (average vs. high verbal intelligence, HR = 1.97, 95% CI 1.05-3.71; low vs. high spelling skills, HR = 2.02, 95% CI 1.16-3.51; low vs. high reading skills, HR = 2.01, 95% CI 1.27-3.17). Associations were still evident, especially for verbal intelligence and reading skills, but hazard ratios were attenuated after adjusting for prenatal and sociodemographic factors at birth (verbal intelligence, HR = 1.97, 95% CI 1.03-3.78; spelling, HR = 1.61, 95% CI 0.90-2.88; reading, HR = 1.67, 95% CI 1.02-2.72).nnCONCLUSIONS: Childhood neurocognitive performance is associated with vulnerability to suicide mortality through middle-adulthood, suggesting that there might be a cognitive diathesis for suicide originating in early childhood. Future studies should examine how multiple domains of childhood cognitive performance contribute to vulnerability to suicide risk, including by increasing risk for social and environmental factors that are associated not only with suicide but also with many types of psychiatric disorders.
Bodhini, Dhanasekaran | Morton, Robert W | Santhakumar, Vanessa | Nakabuye, Mariam | Pomares-Millan, Hugo | Clemmensen, Christoffer | Fitzpatrick, Stephanie L | Guasch-Ferre, Marta | Pankow, James S | Ried-Larsen, Mathias | Franks, Paul W | | Tobias, Deirdre K | Merino, Jordi | Mohan, Viswanathan | Loos, Ruth J F
Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 133, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794109,
title = {Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review},
author = {Dhanasekaran Bodhini and Robert W Morton and Vanessa Santhakumar and Mariam Nakabuye and Hugo Pomares-Millan and Christoffer Clemmensen and Stephanie L Fitzpatrick and Marta Guasch-Ferre and James S Pankow and Mathias Ried-Larsen and Paul W Franks and and Deirdre K Tobias and Jordi Merino and Viswanathan Mohan and Ruth J F Loos},
doi = {10.1038/s43856-023-00363-0},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {133},
abstract = {BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D.nnMETHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier.nnRESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition.nnCONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D.nnMETHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier.nnRESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition.nnCONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.
Lim, Siew | Takele, Wubet Worku | Vesco, Kimberly K | Redman, Leanne M | Hannah, Wesley | Bonham, Maxine P | Chen, Mingling | Chivers, Sian C | Fawcett, Andrea J | Grieger, Jessica A | Habibi, Nahal | Leung, Gloria K W | Liu, Kai | Mekonnen, Eskedar Getie | Pathirana, Maleesa | Quinteros, Alejandra | Taylor, Rachael | Ukke, Gebresilasea G | Zhou, Shao J | | Josefson, Jami
Participant characteristics in the prevention of gestational diabetes as evidence for precision medicine: a systematic review and meta-analysis Journal Article
In: Commun Med (Lond), vol. 3, no. 1, pp. 137, 2023, ISSN: 2730-664X.
Abstract | Links | BibTeX | Tags:
@article{pmid37794119,
title = {Participant characteristics in the prevention of gestational diabetes as evidence for precision medicine: a systematic review and meta-analysis},
author = {Siew Lim and Wubet Worku Takele and Kimberly K Vesco and Leanne M Redman and Wesley Hannah and Maxine P Bonham and Mingling Chen and Sian C Chivers and Andrea J Fawcett and Jessica A Grieger and Nahal Habibi and Gloria K W Leung and Kai Liu and Eskedar Getie Mekonnen and Maleesa Pathirana and Alejandra Quinteros and Rachael Taylor and Gebresilasea G Ukke and Shao J Zhou and and Jami Josefson},
doi = {10.1038/s43856-023-00366-x},
issn = {2730-664X},
year = {2023},
date = {2023-10-01},
journal = {Commun Med (Lond)},
volume = {3},
number = {1},
pages = {137},
abstract = {BACKGROUND: Precision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with responses to interventions in gestational diabetes mellitus (GDM) prevention.nnMETHODS: We searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022.nnRESULTS: From 10347 studies, 116 studies (n = 40940 women) are included. Physical activity results in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Combined diet and physical activity interventions result in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78-1.61]) and in those without a history of GDM than those with unspecified GDM history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions are more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.21 [0.11, 0.40] vs 1.15 [0.86-1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes have no effect on intervention responses.nnCONCLUSIONS: GDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results disaggregated by a priori defined participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Precision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with responses to interventions in gestational diabetes mellitus (GDM) prevention.nnMETHODS: We searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022.nnRESULTS: From 10347 studies, 116 studies (n = 40940 women) are included. Physical activity results in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Combined diet and physical activity interventions result in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78-1.61]) and in those without a history of GDM than those with unspecified GDM history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions are more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.21 [0.11, 0.40] vs 1.15 [0.86-1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes have no effect on intervention responses.nnCONCLUSIONS: GDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results disaggregated by a priori defined participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions.
Urbut, Sarah M | Koyama, Satoshi | Hornsby, Whitney | Bhukar, Rohan | Kheterpal, Sumeet | Truong, Buu | Selvaraj, Margaret S | Neale, Benjamin | O'Donnell, Christopher J | Peloso, Gina M | Natarajan, Pradeep
Bayesian multivariate genetic analysis improves translational insights Journal Article
In: iScience, vol. 26, no. 10, pp. 107854, 2023, ISSN: 2589-0042.
Abstract | Links | BibTeX | Tags:
@article{pmid37766997,
title = {Bayesian multivariate genetic analysis improves translational insights},
author = {Sarah M Urbut and Satoshi Koyama and Whitney Hornsby and Rohan Bhukar and Sumeet Kheterpal and Buu Truong and Margaret S Selvaraj and Benjamin Neale and Christopher J O'Donnell and Gina M Peloso and Pradeep Natarajan},
doi = {10.1016/j.isci.2023.107854},
issn = {2589-0042},
year = {2023},
date = {2023-10-01},
journal = {iScience},
volume = {26},
number = {10},
pages = {107854},
abstract = {While lipid traits are known essential mediators of cardiovascular disease, few approaches have taken advantage of their shared genetic effects. We apply a Bayesian multivariate size estimator, mash, to GWAS of four lipid traits in the Million Veterans Program (MVP) and provide posterior mean and local false sign rates for all effects. These estimates borrow information across traits to improve effect size accuracy. We show that controlling local false sign rates accurately and powerfully identifies replicable genetic associations and that multivariate control furthers the ability to explain complex diseases. Our application yields high concordance between independent datasets, more accurately prioritizes causal genes, and significantly improves polygenic prediction beyond state-of-the-art methods by up to 59% for lipid traits. The use of Bayesian multivariate genetic shrinkage has yet to be applied to human quantitative trait GWAS results, and we present a staged approach to prediction on a polygenic scale.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
While lipid traits are known essential mediators of cardiovascular disease, few approaches have taken advantage of their shared genetic effects. We apply a Bayesian multivariate size estimator, mash, to GWAS of four lipid traits in the Million Veterans Program (MVP) and provide posterior mean and local false sign rates for all effects. These estimates borrow information across traits to improve effect size accuracy. We show that controlling local false sign rates accurately and powerfully identifies replicable genetic associations and that multivariate control furthers the ability to explain complex diseases. Our application yields high concordance between independent datasets, more accurately prioritizes causal genes, and significantly improves polygenic prediction beyond state-of-the-art methods by up to 59% for lipid traits. The use of Bayesian multivariate genetic shrinkage has yet to be applied to human quantitative trait GWAS results, and we present a staged approach to prediction on a polygenic scale.
Misra, Shivani | Ke, Calvin | Srinivasan, Shylaja | Goyal, Alpesh | Nyriyenda, Moffat J | Florez, Jose C | Khunti, Kamlesh | Magliano, Dianna J | Luk, Andrea
Current insights and emerging trends in early-onset type 2 diabetes Journal Article
In: Lancet Diabetes Endocrinol, vol. 11, no. 10, pp. 768–782, 2023, ISSN: 2213-8595.
Abstract | Links | BibTeX | Tags:
@article{pmid37708901,
title = {Current insights and emerging trends in early-onset type 2 diabetes},
author = {Shivani Misra and Calvin Ke and Shylaja Srinivasan and Alpesh Goyal and Moffat J Nyriyenda and Jose C Florez and Kamlesh Khunti and Dianna J Magliano and Andrea Luk},
doi = {10.1016/S2213-8587(23)00225-5},
issn = {2213-8595},
year = {2023},
date = {2023-10-01},
journal = {Lancet Diabetes Endocrinol},
volume = {11},
number = {10},
pages = {768--782},
abstract = {Type 2 diabetes diagnosed in childhood or early adulthood is termed early-onset type 2 diabetes. Cases of early-onset type 2 diabetes are increasing rapidly globally, alongside rising obesity. Compared with a diagnosis later in life, an earlier-onset diagnosis carries an unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and earlier death. Women with early-onset type 2 diabetes also have a higher risk of adverse pregnancy outcomes. The high burden of complications renders individuals with early-onset type 2 diabetes at future risk of multimorbidity and interventions to reverse these concerning trends should be a priority. Within the early-onset cohort, disease pathophysiology and interventions have been better studied in paediatric-onset (<19 years) type 2 diabetes compared to adults; however, young adults aged 19-39 years (a larger number proportionally) are not well characterised and are also invisible in the current evidence base supporting management, which is derived from trials in later-onset type 2 diabetes. Young adults with type 2 diabetes face challenges in self-management that older individuals are less likely to experience (being in education or of working age, higher diabetes distress, and possible obesity-related stigma and diabetes-related stigma). There is a major research gap as to the optimal strategies to deploy in managing type 2 diabetes in adolescents and young adults, given that current models of care appear to not work as well in this age group. In the face of manifold risk factors (obesity, female sex, social deprivation, non-White European ethnicity, and genetic risk factors) prevention strategies with tailored lifestyle interventions, where needed, are likely to have greater success, but more evidence is needed. In this Review, we draw on evidence from both adolescents and young adults to provide a contemporary update on the current insights and emerging trends in early-onset type 2 diabetes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Type 2 diabetes diagnosed in childhood or early adulthood is termed early-onset type 2 diabetes. Cases of early-onset type 2 diabetes are increasing rapidly globally, alongside rising obesity. Compared with a diagnosis later in life, an earlier-onset diagnosis carries an unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and earlier death. Women with early-onset type 2 diabetes also have a higher risk of adverse pregnancy outcomes. The high burden of complications renders individuals with early-onset type 2 diabetes at future risk of multimorbidity and interventions to reverse these concerning trends should be a priority. Within the early-onset cohort, disease pathophysiology and interventions have been better studied in paediatric-onset (<19 years) type 2 diabetes compared to adults; however, young adults aged 19-39 years (a larger number proportionally) are not well characterised and are also invisible in the current evidence base supporting management, which is derived from trials in later-onset type 2 diabetes. Young adults with type 2 diabetes face challenges in self-management that older individuals are less likely to experience (being in education or of working age, higher diabetes distress, and possible obesity-related stigma and diabetes-related stigma). There is a major research gap as to the optimal strategies to deploy in managing type 2 diabetes in adolescents and young adults, given that current models of care appear to not work as well in this age group. In the face of manifold risk factors (obesity, female sex, social deprivation, non-White European ethnicity, and genetic risk factors) prevention strategies with tailored lifestyle interventions, where needed, are likely to have greater success, but more evidence is needed. In this Review, we draw on evidence from both adolescents and young adults to provide a contemporary update on the current insights and emerging trends in early-onset type 2 diabetes.
Kirby, Hannah G | Rehm, Heidi L | Hull, Leland E
An Environmental Scan of Consumer-Initiated Germline Genetic Testing for Health Risks Journal Article
In: Mayo Clin Proc, vol. 98, no. 10, pp. 1529–1543, 2023, ISSN: 1942-5546.
Abstract | Links | BibTeX | Tags:
@article{pmid37632486,
title = {An Environmental Scan of Consumer-Initiated Germline Genetic Testing for Health Risks},
author = {Hannah G Kirby and Heidi L Rehm and Leland E Hull},
doi = {10.1016/j.mayocp.2023.04.008},
issn = {1942-5546},
year = {2023},
date = {2023-10-01},
journal = {Mayo Clin Proc},
volume = {98},
number = {10},
pages = {1529--1543},
abstract = {As patient access to laboratory testing outside the clinic grows, health care providers can expect to confront increasing questions about the utility and interpretation of consumer-initiated genetic testing for health risks. We sought to characterize the marketplace diversity of consumer-initiated germline genetic testing options. An environmental scan was conducted to identify germline genetic testing companies that offer testing for at least one diagnosable health condition and are available for purchase by consumers in the US market without a visit to one's health care provider. We limited our scope to tests available between October 1, 2019, and September 30, 2021. We characterized variability in the content and processes used by 21 companies offering 74 distinct test products that met our inclusion and exclusion criteria. A minority (8 of 21 companies) offered tests that assessed the presence of at least 1 US Centers for Disease Control and Prevention Tier 1 condition for which detection can impact an individual's clinical care and for which evidence-based guidelines for detection and management exist.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
As patient access to laboratory testing outside the clinic grows, health care providers can expect to confront increasing questions about the utility and interpretation of consumer-initiated genetic testing for health risks. We sought to characterize the marketplace diversity of consumer-initiated germline genetic testing options. An environmental scan was conducted to identify germline genetic testing companies that offer testing for at least one diagnosable health condition and are available for purchase by consumers in the US market without a visit to one's health care provider. We limited our scope to tests available between October 1, 2019, and September 30, 2021. We characterized variability in the content and processes used by 21 companies offering 74 distinct test products that met our inclusion and exclusion criteria. A minority (8 of 21 companies) offered tests that assessed the presence of at least 1 US Centers for Disease Control and Prevention Tier 1 condition for which detection can impact an individual's clinical care and for which evidence-based guidelines for detection and management exist.
Ward, Scott K | Wadley, Alexandrea | Tsai, Chun-Hui Anne | Benke, Paul J | Emrick, Lisa | Fisher, Kristen | Houck, Kimberly M | Dai, Hongzheng | | Sacoto, Maria J Guillen | Craigen, William | Glaser, Kimberly | Murdock, David R | Rohena, Luis | Diderich, Karin E M | Bruggenwirth, Hennie T | Lee, Brendan | Bacino, Carlos | Burrage, Lindsay C | Rosenfeld, Jill A
In: Am J Med Genet A, 2023, ISSN: 1552-4833.
Abstract | Links | BibTeX | Tags:
@article{pmid37743782,
title = {De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities},
author = {Scott K Ward and Alexandrea Wadley and Chun-Hui Anne Tsai and Paul J Benke and Lisa Emrick and Kristen Fisher and Kimberly M Houck and Hongzheng Dai and and Maria J Guillen Sacoto and William Craigen and Kimberly Glaser and David R Murdock and Luis Rohena and Karin E M Diderich and Hennie T Bruggenwirth and Brendan Lee and Carlos Bacino and Lindsay C Burrage and Jill A Rosenfeld},
doi = {10.1002/ajmg.a.63399},
issn = {1552-4833},
year = {2023},
date = {2023-09-01},
journal = {Am J Med Genet A},
abstract = {The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.
Kelly, Dearbhla M | Georgakis, Marios K | Franceschini, Nora | Blacker, Deborah | Viswanathan, Anand | Anderson, Christopher D
Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis Journal Article
In: Neurology, 2023, ISSN: 1526-632X.
Abstract | Links | BibTeX | Tags:
@article{pmid37775316,
title = {Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis},
author = {Dearbhla M Kelly and Marios K Georgakis and Nora Franceschini and Deborah Blacker and Anand Viswanathan and Christopher D Anderson},
doi = {10.1212/WNL.0000000000207852},
issn = {1526-632X},
year = {2023},
date = {2023-09-01},
journal = {Neurology},
abstract = {BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension and cerebrovascular disease phenotypes.nnMETHODS: We used data from genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischaemic stroke and its subtypes, and intracerebral haemorrhage [ICH). We then conducted univariable, multivariable and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension.nnRESULTS: Univariable Mendelian randomization revealed associations between genetically determined lower eGFR and risk of all stroke (OR per 1-log decrement in eGFR, 1.77; 95% CI, 1.31-2.40; p<0.001), ischaemic stroke (OR, 1.81; 95% CI, 1.31-2.51; p<0.001), and most strongly with large artery stroke (LAS) (OR, 3.00; 95% CI, 1.33-6.75; p=0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR, 1.98; 95% CI, 1.39-2.82; p<0.001 for AS; OR, 2.16; 95% CI, 1.48-3.17; p<0.001 for IS; OR, 4.35; 95% CI, 1.84-10.27; p=0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7-16.8%], 6.6% [0.8-18.3%] and 7.2% [0.5-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (Weighted median, MR-Egger regression).nnDISCUSSION: Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension and cerebrovascular disease phenotypes.nnMETHODS: We used data from genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischaemic stroke and its subtypes, and intracerebral haemorrhage [ICH). We then conducted univariable, multivariable and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension.nnRESULTS: Univariable Mendelian randomization revealed associations between genetically determined lower eGFR and risk of all stroke (OR per 1-log decrement in eGFR, 1.77; 95% CI, 1.31-2.40; p<0.001), ischaemic stroke (OR, 1.81; 95% CI, 1.31-2.51; p<0.001), and most strongly with large artery stroke (LAS) (OR, 3.00; 95% CI, 1.33-6.75; p=0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR, 1.98; 95% CI, 1.39-2.82; p<0.001 for AS; OR, 2.16; 95% CI, 1.48-3.17; p<0.001 for IS; OR, 4.35; 95% CI, 1.84-10.27; p=0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7-16.8%], 6.6% [0.8-18.3%] and 7.2% [0.5-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (Weighted median, MR-Egger regression).nnDISCUSSION: Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.
Eyre, Harris A | Stirland, Lucy E | Jeste, Dilip V | Reynolds, Charles F | Berk, Michael | Ibanez, Agustin | Dawson, Walter D | Lawlor, Brian | Leroi, Iracema | Yaffe, Kristine | Gatchel, Jennifer R | Karp, Jordan F | Newhouse, Paul | Rosand, Jonathan | Letourneau, Nicole | Bayen, Eleonore | Farina, Francesca | Booi, Laura | Devanand, Devangere P | Mintzer, Jacobo | Madigan, Sheri | Jayapurwala, Inez | Wong, Stephen T C | Falcoa, Veronica Podence | Cummings, Jeffrey L | Reichman, William | Lock, Sarah Lenz | Bennett, Marc | Ahuja, Rajiv | Steffens, David C | Elkind, Mitchell S V | Lavretsky, Helen
Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations Journal Article
In: Am J Geriatr Psychiatry, 2023, ISSN: 1545-7214.
Abstract | Links | BibTeX | Tags:
@article{pmid37798224,
title = {Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations},
author = {Harris A Eyre and Lucy E Stirland and Dilip V Jeste and Charles F Reynolds and Michael Berk and Agustin Ibanez and Walter D Dawson and Brian Lawlor and Iracema Leroi and Kristine Yaffe and Jennifer R Gatchel and Jordan F Karp and Paul Newhouse and Jonathan Rosand and Nicole Letourneau and Eleonore Bayen and Francesca Farina and Laura Booi and Devangere P Devanand and Jacobo Mintzer and Sheri Madigan and Inez Jayapurwala and Stephen T C Wong and Veronica Podence Falcoa and Jeffrey L Cummings and William Reichman and Sarah Lenz Lock and Marc Bennett and Rajiv Ahuja and David C Steffens and Mitchell S V Elkind and Helen Lavretsky},
doi = {10.1016/j.jagp.2023.09.013},
issn = {1545-7214},
year = {2023},
date = {2023-09-01},
journal = {Am J Geriatr Psychiatry},
abstract = {This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.
Manning, Alisa | Sevilla-González, Magdalena | Smith, Kirk | Wang, Ningyuan | Jensen, Aubrey | Litkowski, Elizabeth | Kim, Hyunkyung | DiCorpo, Daniel | Westerman, Kenneth | Cui, Jinrui | Liu, Ching-Ti | Yu, Chenglong | McNeil, John | Lacaze, Paul | Chang, Kyong-Mi | Tsao, Phil | Phillips, Lawrence | Goodarzi, Mark | Sladek, Rob | Rotter, Jerome | Dupuis, Josee | Florez, Jose | Merino, Jordi | Meigs, James | Zhou, Jin | Raghavan, Sridharan | Udler, Miriam
2023.
Abstract | Links | BibTeX | Tags:
@misc{pmid37790568,
title = {Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin},
author = {Alisa Manning and Magdalena Sevilla-González and Kirk Smith and Ningyuan Wang and Aubrey Jensen and Elizabeth Litkowski and Hyunkyung Kim and Daniel DiCorpo and Kenneth Westerman and Jinrui Cui and Ching-Ti Liu and Chenglong Yu and John McNeil and Paul Lacaze and Kyong-Mi Chang and Phil Tsao and Lawrence Phillips and Mark Goodarzi and Rob Sladek and Jerome Rotter and Josee Dupuis and Jose Florez and Jordi Merino and James Meigs and Jin Zhou and Sridharan Raghavan and Miriam Udler},
doi = {10.21203/rs.3.rs-3317661/v1},
year = {2023},
date = {2023-09-01},
journal = {Res Sq},
abstract = {Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities. We identified seven distinctive genetic clusters representing different physiologic mechanisms leading to rising FI levels, ranging from clusters of variants with effects on increased FI, but without increased risk of T2D (non-diabetogenic hyperinsulinemia), to clusters of variants that increase FI and T2D risk with demonstrated strong effects on body fat distribution, liver, lipid, and inflammatory processes (diabetogenic hyperinsulinemia). We generated cluster-specific polygenic scores in 1,104,258 individuals from five multi-ancestry cohorts to show that the clusters differed in associations with cardiometabolic traits. Among clusters characterized by non-diabetogenic hyperinsulinemia, there was both increased and decreased risk of coronary artery disease despite the non-increased risk of T2D. Similarly, the clusters characterized by diabetogenic hyperinsulinemia were associated with an increased risk of T2D, yet had differing risks of cardiovascular conditions, including coronary artery disease, myocardial infarction, and stroke. The strongest cluster-T2D associations were observed with the same direction of effect in non-Hispanic Black, Hispanic, non-Hispanic White, and non-Hispanic East Asian populations. These genetic clusters provide important insights into granular metabolic processes underlying the physiology of hyperinsulinemia, notably highlighting specific processes that decouple increasing FI levels from T2D and cardiovascular risk. Our findings suggest that increasing FI levels are not invariably associated with adverse cardiometabolic outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities. We identified seven distinctive genetic clusters representing different physiologic mechanisms leading to rising FI levels, ranging from clusters of variants with effects on increased FI, but without increased risk of T2D (non-diabetogenic hyperinsulinemia), to clusters of variants that increase FI and T2D risk with demonstrated strong effects on body fat distribution, liver, lipid, and inflammatory processes (diabetogenic hyperinsulinemia). We generated cluster-specific polygenic scores in 1,104,258 individuals from five multi-ancestry cohorts to show that the clusters differed in associations with cardiometabolic traits. Among clusters characterized by non-diabetogenic hyperinsulinemia, there was both increased and decreased risk of coronary artery disease despite the non-increased risk of T2D. Similarly, the clusters characterized by diabetogenic hyperinsulinemia were associated with an increased risk of T2D, yet had differing risks of cardiovascular conditions, including coronary artery disease, myocardial infarction, and stroke. The strongest cluster-T2D associations were observed with the same direction of effect in non-Hispanic Black, Hispanic, non-Hispanic White, and non-Hispanic East Asian populations. These genetic clusters provide important insights into granular metabolic processes underlying the physiology of hyperinsulinemia, notably highlighting specific processes that decouple increasing FI levels from T2D and cardiovascular risk. Our findings suggest that increasing FI levels are not invariably associated with adverse cardiometabolic outcomes.
Zeldovich, Marina | Bockhop, Fabian | Covic, Amra | Mueller, Isabelle | Polinder, Suzanne | Mikolic, Ana | van der Vlegel, Marjolein | von Steinbuechel and, Nicole
In: J Patient Rep Outcomes, vol. 7, no. 1, pp. 90, 2023, ISSN: 2509-8020.
Abstract | Links | BibTeX | Tags:
@article{pmid37682406,
title = {Factorial validity and comparability of the six translations of the Rivermead Post-Concussion Symptoms Questionnaire translations: results from the CENTER-TBI study},
author = {Marina Zeldovich and Fabian Bockhop and Amra Covic and Isabelle Mueller and Suzanne Polinder and Ana Mikolic and Marjolein van der Vlegel and Nicole von Steinbuechel and },
doi = {10.1186/s41687-023-00632-5},
issn = {2509-8020},
year = {2023},
date = {2023-09-01},
journal = {J Patient Rep Outcomes},
volume = {7},
number = {1},
pages = {90},
abstract = {BACKGROUND: Comparison of patient-reported outcomes in multilingual studies requires evidence of the equivalence of translated versions of the questionnaires. The present study examines the factorial validity and comparability of six language versions of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) administered to individuals following traumatic brain injury (TBI) in the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) study.nnMETHODS: Six competing RPQ models were estimated using data from Dutch (n = 597), English (n = 223), Finnish (n = 213), Italian (n = 268), Norwegian (n = 263), and Spanish (n = 254) language samples recruited six months after injury. To determine whether the same latent construct was measured by the best-fitting model across languages and TBI severity groups (mild/moderate vs. severe), measurement invariance (MI) was tested using a confirmatory factor analysis framework.nnRESULTS: The results did not indicate a violation of the MI assumption. The six RPQ translations were largely comparable across languages and were able to capture the same construct across TBI severity groups. The three-factor solution comprising emotional, cognitive, and somatic factors provided the best fit with the following indices for the total sample: χ (101) = 647.04, [Formula: see text]= 6.41, p < 0.001, CFI = 0.995, TLI = 0.994, RMSEA = 0.055, CI[0.051, 0.059], SRMR = 0.051.nnCONCLUSION: The RPQ can be used in international research and clinical settings, allowing direct comparisons of scores across languages analyzed within the full spectrum of TBI severity. To strengthen the aggregated applicability across languages, further analyses of the utility of the response scale and comparisons between different translations of the RPQ at the item level are recommended.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Comparison of patient-reported outcomes in multilingual studies requires evidence of the equivalence of translated versions of the questionnaires. The present study examines the factorial validity and comparability of six language versions of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) administered to individuals following traumatic brain injury (TBI) in the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) study.nnMETHODS: Six competing RPQ models were estimated using data from Dutch (n = 597), English (n = 223), Finnish (n = 213), Italian (n = 268), Norwegian (n = 263), and Spanish (n = 254) language samples recruited six months after injury. To determine whether the same latent construct was measured by the best-fitting model across languages and TBI severity groups (mild/moderate vs. severe), measurement invariance (MI) was tested using a confirmatory factor analysis framework.nnRESULTS: The results did not indicate a violation of the MI assumption. The six RPQ translations were largely comparable across languages and were able to capture the same construct across TBI severity groups. The three-factor solution comprising emotional, cognitive, and somatic factors provided the best fit with the following indices for the total sample: χ (101) = 647.04, [Formula: see text]= 6.41, p < 0.001, CFI = 0.995, TLI = 0.994, RMSEA = 0.055, CI[0.051, 0.059], SRMR = 0.051.nnCONCLUSION: The RPQ can be used in international research and clinical settings, allowing direct comparisons of scores across languages analyzed within the full spectrum of TBI severity. To strengthen the aggregated applicability across languages, further analyses of the utility of the response scale and comparisons between different translations of the RPQ at the item level are recommended.
Schuermans, Art | Ardissino, Maddalena | Nauffal, Victor | Khurshid, Shaan | Pirruccello, James P | Ellinor, Patrick T | Lewandowski, Adam J | Natarajan, Pradeep | Honigberg, Michael C
Genetically Predicted Gestational Age and Birth Weight Are Associated With Cardiac and Pulmonary Vascular Remodeling in Adulthood Journal Article
In: Eur J Prev Cardiol, 2023, ISSN: 2047-4881.
@article{pmid37694688,
title = {Genetically Predicted Gestational Age and Birth Weight Are Associated With Cardiac and Pulmonary Vascular Remodeling in Adulthood},
author = {Art Schuermans and Maddalena Ardissino and Victor Nauffal and Shaan Khurshid and James P Pirruccello and Patrick T Ellinor and Adam J Lewandowski and Pradeep Natarajan and Michael C Honigberg},
doi = {10.1093/eurjpc/zwad296},
issn = {2047-4881},
year = {2023},
date = {2023-09-01},
journal = {Eur J Prev Cardiol},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hu, Jianhong | Korchina, Viktoriya | Zouk, Hana | Harden, Maegan V | Murdock, David | Macbeth, Alyssa | Harrison, Steven M | Lennon, Niall | Kovar, Christie | Balasubramanian, Adithya | Zhang, Lan | Chandanavelli, Gauthami | Pasham, Divya | Rowley, Robb | Wiley, Ken | Smith, Maureen E | Gordon, Adam | Jarvik, Gail P | Sleiman, Patrick | Kelly, Melissa A | Bland, Harris T | Murugan, Mullai | Venner, Eric | Boerwinkle, Eric | Prows, Cynthia | Mahanta, Lisa | Rehm, Heidi L | Gibbs, Richard A | Muzny, Donna M
Genetic Sex Validation for Sample Tracking in Clinical Testing Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@misc{pmid37790445,
title = {Genetic Sex Validation for Sample Tracking in Clinical Testing},
author = {Jianhong Hu and Viktoriya Korchina and Hana Zouk and Maegan V Harden and David Murdock and Alyssa Macbeth and Steven M Harrison and Niall Lennon and Christie Kovar and Adithya Balasubramanian and Lan Zhang and Gauthami Chandanavelli and Divya Pasham and Robb Rowley and Ken Wiley and Maureen E Smith and Adam Gordon and Gail P Jarvik and Patrick Sleiman and Melissa A Kelly and Harris T Bland and Mullai Murugan and Eric Venner and Eric Boerwinkle and Cynthia Prows and Lisa Mahanta and Heidi L Rehm and Richard A Gibbs and Donna M Muzny},
doi = {10.21203/rs.3.rs-3304685/v1},
year = {2023},
date = {2023-09-01},
journal = {Res Sq},
abstract = {Objective Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. Results Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors, samples from transgender participants and stem cell or bone marrow transplant patients along with undetermined sample mix-ups.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Objective Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. Results Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors, samples from transgender participants and stem cell or bone marrow transplant patients along with undetermined sample mix-ups.
Toikumo, Sylvanus | Jennings, Mariela V | Pham, Benjamin K | Lee, Hyunjoon | Mallard, Travis T | Bianchi, Sevim B | Meredith, John J | Vilar-Ribó, Laura | Xu, Heng | Hatoum, Alexander S | Johnson, Emma C | Pazdernik, Vanessa | Jinwala, Zeal | Pakala, Shreya R | Leger, Brittany S | Niarchou, Maria | Ehinmowo, Michael | | | Jenkins, Greg D | Batzler, Anthony | Pendegraft, Richard | Palmer, Abraham A | Zhou, Hang | Biernacka, Joanna M | Coombes, Brandon J | Gelernter, Joel | Xu, Ke | Hancock, Dana B | Nancy, Cox J | Smoller, Jordan W | Davis, Lea K | Justice, Amy C | Kranzler, Henry R | Kember, Rachel L | Sanchez-Roige, Sandra
2023.
Abstract | Links | BibTeX | Tags:
@misc{pmid37034728,
title = {Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes},
author = {Sylvanus Toikumo and Mariela V Jennings and Benjamin K Pham and Hyunjoon Lee and Travis T Mallard and Sevim B Bianchi and John J Meredith and Laura Vilar-Ribó and Heng Xu and Alexander S Hatoum and Emma C Johnson and Vanessa Pazdernik and Zeal Jinwala and Shreya R Pakala and Brittany S Leger and Maria Niarchou and Michael Ehinmowo and and and Greg D Jenkins and Anthony Batzler and Richard Pendegraft and Abraham A Palmer and Hang Zhou and Joanna M Biernacka and Brandon J Coombes and Joel Gelernter and Ke Xu and Dana B Hancock and Cox J Nancy and Jordan W Smoller and Lea K Davis and Amy C Justice and Henry R Kranzler and Rachel L Kember and Sandra Sanchez-Roige},
doi = {10.1101/2023.03.27.23287713},
year = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {Tobacco use disorder ( ) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies ( ) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, ) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Tobacco use disorder ( ) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies ( ) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, ) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.
Shashi, Vandana | Schoch, Kelly | Ganetzky, Rebecca | Kranz, Peter G | Sondheimer, Neal | Markert, M Louise | Cope, Heidi | Sadeghpour, Azita | Roehrs, Philip | Arbogast, Thomas | Muraresku, Colleen | | Tyndall, Amanda V | Esser, Michael J | Woodward, Kristine E | Au, Billie Ping-Yee | Parboosingh, Jillian S | Lamont, Ryan E | Bernier, Francois P | Wright, Nicola A M | Benseler, Susa M | Parsons, Simon J | El-Dairi, Mays | Smith, Edward C | Valdez, Purnima | Tennison, Michael | Innes, A Micheil | Davis, Erica E
In: Genet Med, vol. 25, no. 9, pp. 100897, 2023, ISSN: 1530-0366.
Abstract | Links | BibTeX | Tags:
@article{pmid37191094,
title = {Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy},
author = {Vandana Shashi and Kelly Schoch and Rebecca Ganetzky and Peter G Kranz and Neal Sondheimer and M Louise Markert and Heidi Cope and Azita Sadeghpour and Philip Roehrs and Thomas Arbogast and Colleen Muraresku and and Amanda V Tyndall and Michael J Esser and Kristine E Woodward and Billie Ping-Yee Au and Jillian S Parboosingh and Ryan E Lamont and Francois P Bernier and Nicola A M Wright and Susa M Benseler and Simon J Parsons and Mays El-Dairi and Edward C Smith and Purnima Valdez and Michael Tennison and A Micheil Innes and Erica E Davis},
doi = {10.1016/j.gim.2023.100897},
issn = {1530-0366},
year = {2023},
date = {2023-09-01},
journal = {Genet Med},
volume = {25},
number = {9},
pages = {100897},
abstract = {PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.nnMETHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.nnRESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family.nnCONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.nnMETHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.nnRESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family.nnCONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1471–1482, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@article{pmid37653029,
title = {GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture},
author = { },
doi = {10.1038/s41588-023-01485-w},
issn = {1546-1718},
year = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1471--1482},
abstract = {Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
Alghamdi, Malak Ali | O'Donnell-Luria, Anne | Almontashiri, Naif A | AlAali, Wajeih Y | Ali, Hebatallah H | Levy, Harvey L
Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman Miscellaneous
2023, ISSN: 2192-8304.
Abstract | Links | BibTeX | Tags:
@misc{pmid37701331,
title = {Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman},
author = {Malak Ali Alghamdi and Anne O'Donnell-Luria and Naif A Almontashiri and Wajeih Y AlAali and Hebatallah H Ali and Harvey L Levy},
doi = {10.1002/jmd2.12384},
issn = {2192-8304},
year = {2023},
date = {2023-09-01},
journal = {JIMD Rep},
volume = {64},
number = {5},
pages = {312--316},
abstract = {Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH). If untreated by dietary restriction of phenylalanine intake, impaired postnatal cognitive development results from the neurotoxic effects of excessive phenylalanine (Phe). Signs and symptoms include severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly. Maternal PKU syndrome refers to fetal damage resulting in congenital abnormalities when the mother has untreated PKU during pregnancy. Here, we report an intellectually normal 32-year-old female who presented with recurrent pregnancy loss and two neonatal deaths with congenital heart disease, microcephaly, intrauterine growth restriction, and respiratory distress. She was diagnosed with PKU through exome sequencing performed for carrier testing with a homozygous pathogenic variant in the PAH gene, c.169_171del, p.(Glu57del) that is associated with classical PKU. Consistent with the genetic finding, she had a markedly increased plasma phenylalanine concentration of 1642 μmol/L (normal <100). This case demonstrates that recurrent pregnancy loss due to untreated maternal PKU may present as an initial finding in otherwise unsuspected classical PKU and illustrates that extreme degrees of variable expressivity may occur in classical PKU. Moreover, this case illustrates the value of genomic sequencing of women who experience recurrent pregnancy loss or neonatal anomalies.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH). If untreated by dietary restriction of phenylalanine intake, impaired postnatal cognitive development results from the neurotoxic effects of excessive phenylalanine (Phe). Signs and symptoms include severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly. Maternal PKU syndrome refers to fetal damage resulting in congenital abnormalities when the mother has untreated PKU during pregnancy. Here, we report an intellectually normal 32-year-old female who presented with recurrent pregnancy loss and two neonatal deaths with congenital heart disease, microcephaly, intrauterine growth restriction, and respiratory distress. She was diagnosed with PKU through exome sequencing performed for carrier testing with a homozygous pathogenic variant in the PAH gene, c.169_171del, p.(Glu57del) that is associated with classical PKU. Consistent with the genetic finding, she had a markedly increased plasma phenylalanine concentration of 1642 μmol/L (normal <100). This case demonstrates that recurrent pregnancy loss due to untreated maternal PKU may present as an initial finding in otherwise unsuspected classical PKU and illustrates that extreme degrees of variable expressivity may occur in classical PKU. Moreover, this case illustrates the value of genomic sequencing of women who experience recurrent pregnancy loss or neonatal anomalies.
Recto, Kathryn | Kachroo, Priyadarshini | Huan, Tianxiao | Berg, David Van Den | Lee, Gha Young | Bui, Helena | Lee, Dong Heon | Gereige, Jessica | Yao, Chen | Hwang, Shih-Jen | Joehanes, Roby | Weiss, Scott T | | O'Connor, George T | Levy, Daniel | DeMeo, Dawn L
Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma Journal Article
In: EBioMedicine, vol. 95, pp. 104758, 2023, ISSN: 2352-3964.
Abstract | Links | BibTeX | Tags:
@article{pmid37598461,
title = {Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma},
author = {Kathryn Recto and Priyadarshini Kachroo and Tianxiao Huan and David Van Den Berg and Gha Young Lee and Helena Bui and Dong Heon Lee and Jessica Gereige and Chen Yao and Shih-Jen Hwang and Roby Joehanes and Scott T Weiss and and George T O'Connor and Daniel Levy and Dawn L DeMeo},
doi = {10.1016/j.ebiom.2023.104758},
issn = {2352-3964},
year = {2023},
date = {2023-09-01},
journal = {EBioMedicine},
volume = {95},
pages = {104758},
abstract = {BACKGROUND: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.nnMETHODS: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables.nnFINDINGS: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets.nnINTERPRETATION: By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels.nnFUNDING: US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.nnMETHODS: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables.nnFINDINGS: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets.nnINTERPRETATION: By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels.nnFUNDING: US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.
Harisinghani, Ayesha | Dhand, Amar | Steffensen, Ellen Hollands | Skotko, Brian G
Sustainability of personal social networks of people with Down syndrome Journal Article
In: Am J Med Genet C Semin Med Genet, pp. e32064, 2023, ISSN: 1552-4876.
Abstract | Links | BibTeX | Tags:
@article{pmid37740458,
title = {Sustainability of personal social networks of people with Down syndrome},
author = {Ayesha Harisinghani and Amar Dhand and Ellen Hollands Steffensen and Brian G Skotko},
doi = {10.1002/ajmg.c.32064},
issn = {1552-4876},
year = {2023},
date = {2023-09-01},
journal = {Am J Med Genet C Semin Med Genet},
pages = {e32064},
abstract = {Research continues to demonstrate that the characteristics of one's social network could have an impact on the development of Alzheimer's disease. Given the predisposition of people with Down syndrome to develop Alzheimer's disease, analysis of their social networks has become an emerging focus. Previous pilot research demonstrated that the personal networks of people with DS could be quantitatively analyzed, with no difference between self-report and parent-proxy report. This manuscript focuses on a 12-month follow-up period with the same original participants (24 adults with Down syndrome). Their social networks demonstrated sustainability, but not improvement, as reported by people with DS (mean network size: 8.88; mean density: 0.73; mean constraint: 0.44; mean effective size: 3.58; mean max degree: 6.04; mean degree: 4.78) and their proxies (mean network size: 7.90; mean density: 0.82; mean constraint: 53.13; mean effective size: 2.87; mean max degree: 5.19; mean degree: 4.30). Intentional and continued efforts are likely needed in order to improve the social network measures of people with Down syndrome.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Research continues to demonstrate that the characteristics of one's social network could have an impact on the development of Alzheimer's disease. Given the predisposition of people with Down syndrome to develop Alzheimer's disease, analysis of their social networks has become an emerging focus. Previous pilot research demonstrated that the personal networks of people with DS could be quantitatively analyzed, with no difference between self-report and parent-proxy report. This manuscript focuses on a 12-month follow-up period with the same original participants (24 adults with Down syndrome). Their social networks demonstrated sustainability, but not improvement, as reported by people with DS (mean network size: 8.88; mean density: 0.73; mean constraint: 0.44; mean effective size: 3.58; mean max degree: 6.04; mean degree: 4.78) and their proxies (mean network size: 7.90; mean density: 0.82; mean constraint: 53.13; mean effective size: 2.87; mean max degree: 5.19; mean degree: 4.30). Intentional and continued efforts are likely needed in order to improve the social network measures of people with Down syndrome.
Kerimov, Nurlan | Tambets, Ralf | Hayhurst, James D | Rahu, Ida | Kolberg, Peep | Raudvere, Uku | Kuzmin, Ivan | Chowdhary, Anshika | Vija, Andreas | Teras, Hans J | Kanai, Masahiro | Ulirsch, Jacob | Ryten, Mina | Hardy, John | Guelfi, Sebastian | Trabzuni, Daniah | Kim-Hellmuth, Sarah | Rayner, William | Finucane, Hilary | Peterson, Hedi | Mosaku, Abayomi | Parkinson, Helen | Alasoo, Kaur
eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs Journal Article
In: PLoS Genet, vol. 19, no. 9, pp. e1010932, 2023, ISSN: 1553-7404.
Abstract | Links | BibTeX | Tags:
@article{pmid37721944,
title = {eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs},
author = {Nurlan Kerimov and Ralf Tambets and James D Hayhurst and Ida Rahu and Peep Kolberg and Uku Raudvere and Ivan Kuzmin and Anshika Chowdhary and Andreas Vija and Hans J Teras and Masahiro Kanai and Jacob Ulirsch and Mina Ryten and John Hardy and Sebastian Guelfi and Daniah Trabzuni and Sarah Kim-Hellmuth and William Rayner and Hilary Finucane and Hedi Peterson and Abayomi Mosaku and Helen Parkinson and Kaur Alasoo},
doi = {10.1371/journal.pgen.1010932},
issn = {1553-7404},
year = {2023},
date = {2023-09-01},
journal = {PLoS Genet},
volume = {19},
number = {9},
pages = {e1010932},
abstract = {The eQTL Catalogue is an open database of uniformly processed human molecular quantitative trait loci (QTLs). We are continuously updating the resource to further increase its utility for interpreting genetic associations with complex traits. Over the past two years, we have increased the number of uniformly processed studies from 21 to 31 and added X chromosome QTLs for 19 compatible studies. We have also implemented Leafcutter to directly identify splice-junction usage QTLs in all RNA sequencing datasets. Finally, to improve the interpretability of transcript-level QTLs, we have developed static QTL coverage plots that visualise the association between the genotype and average RNA sequencing read coverage in the region for all 1.7 million fine mapped associations. To illustrate the utility of these updates to the eQTL Catalogue, we performed colocalisation analysis between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. Although most GWAS loci colocalised both with eQTLs and transcript-level QTLs, we found that visual inspection could sometimes be used to distinguish primary splicing QTLs from those that appear to be secondary consequences of large-effect gene expression QTLs. While these visually confirmed primary splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The eQTL Catalogue is an open database of uniformly processed human molecular quantitative trait loci (QTLs). We are continuously updating the resource to further increase its utility for interpreting genetic associations with complex traits. Over the past two years, we have increased the number of uniformly processed studies from 21 to 31 and added X chromosome QTLs for 19 compatible studies. We have also implemented Leafcutter to directly identify splice-junction usage QTLs in all RNA sequencing datasets. Finally, to improve the interpretability of transcript-level QTLs, we have developed static QTL coverage plots that visualise the association between the genotype and average RNA sequencing read coverage in the region for all 1.7 million fine mapped associations. To illustrate the utility of these updates to the eQTL Catalogue, we performed colocalisation analysis between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. Although most GWAS loci colocalised both with eQTLs and transcript-level QTLs, we found that visual inspection could sometimes be used to distinguish primary splicing QTLs from those that appear to be secondary consequences of large-effect gene expression QTLs. While these visually confirmed primary splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases.
Scammell, B H | Tchio, C | Song, Y | Nishiyama, T | Louie, T L | Dashti, H S | Nakatochi, M | Zee, P C | Daghlas, I | Momozawa, Y | Cai, J | Ollila, H M | Redline, S | Wakai, K | Sofer, T | Suzuki, S | Lane, J M | Saxena, R
Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration Journal Article
In: Hum Mol Genet, vol. 32, no. 18, pp. 2797–2807, 2023, ISSN: 1460-2083.
Abstract | Links | BibTeX | Tags:
@article{pmid37384397,
title = {Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration},
author = {B H Scammell and C Tchio and Y Song and T Nishiyama and T L Louie and H S Dashti and M Nakatochi and P C Zee and I Daghlas and Y Momozawa and J Cai and H M Ollila and S Redline and K Wakai and T Sofer and S Suzuki and J M Lane and R Saxena},
doi = {10.1093/hmg/ddad101},
issn = {1460-2083},
year = {2023},
date = {2023-09-01},
journal = {Hum Mol Genet},
volume = {32},
number = {18},
pages = {2797--2807},
abstract = {Both short (≤6 h per night) and long sleep duration (≥9 h per night) are associated with increased risk of chronic diseases. Despite evidence linking habitual sleep duration and risk of disease, the genetic determinants of sleep duration in the general population are poorly understood, especially outside of European (EUR) populations. Here, we report that a polygenic score of 78 European ancestry sleep duration single-nucleotide polymorphisms (SNPs) is associated with sleep duration in an African (n = 7288; P = 0.003), an East Asian (n = 13 618; P = 6 × 10-4) and a South Asian (n = 7485; P = 0.025) genetic ancestry cohort, but not in a Hispanic/Latino cohort (n = 8726; P = 0.71). Furthermore, in a pan-ancestry (N = 483 235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 73 loci are associated with genome-wide statistical significance. Follow-up of five loci (near HACD2, COG5, PRR12, SH3RF1 and KCNQ5) identified expression-quantitative trait loci for PRR12 and COG5 in brain tissues and pleiotropic associations with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Both short (≤6 h per night) and long sleep duration (≥9 h per night) are associated with increased risk of chronic diseases. Despite evidence linking habitual sleep duration and risk of disease, the genetic determinants of sleep duration in the general population are poorly understood, especially outside of European (EUR) populations. Here, we report that a polygenic score of 78 European ancestry sleep duration single-nucleotide polymorphisms (SNPs) is associated with sleep duration in an African (n = 7288; P = 0.003), an East Asian (n = 13 618; P = 6 × 10-4) and a South Asian (n = 7485; P = 0.025) genetic ancestry cohort, but not in a Hispanic/Latino cohort (n = 8726; P = 0.71). Furthermore, in a pan-ancestry (N = 483 235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 73 loci are associated with genome-wide statistical significance. Follow-up of five loci (near HACD2, COG5, PRR12, SH3RF1 and KCNQ5) identified expression-quantitative trait loci for PRR12 and COG5 in brain tissues and pleiotropic associations with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.
Lagou, Vasiliki | Jiang, Longda | Ulrich, Anna | Zudina, Liudmila | González, Karla Sofia Gutiérrez | Balkhiyarova, Zhanna | Faggian, Alessia | Maina, Jared G | Chen, Shiqian | Todorov, Petar V | Sharapov, Sodbo | David, Alessia | Marullo, Letizia | Mägi, Reedik | Rujan, Roxana-Maria | Ahlqvist, Emma | Thorleifsson, Gudmar | Gao, Ηe | Εvangelou, Εvangelos | Benyamin, Beben | Scott, Robert A | Isaacs, Aaron | Zhao, Jing Hua | Willems, Sara M | Johnson, Toby | Gieger, Christian | Grallert, Harald | Meisinger, Christa | Müller-Nurasyid, Martina | Strawbridge, Rona J | Goel, Anuj | Rybin, Denis | Albrecht, Eva | Jackson, Anne U | Stringham, Heather M | Corrêa, Ivan R | Farber-Eger, Eric | Steinthorsdottir, Valgerdur | Uitterlinden, André G | Munroe, Patricia B | Brown, Morris J | Schmidberger, Julian | Holmen, Oddgeir | Thorand, Barbara | Hveem, Kristian | Wilsgaard, Tom | Mohlke, Karen L | Wang, Zhe | | Shmeliov, Aleksey | den Hoed, Marcel | Loos, Ruth J F | Kratzer, Wolfgang | Haenle, Mark | Koenig, Wolfgang | Boehm, Bernhard O | Tan, Tricia M | Tomas, Alejandra | Salem, Victoria | Barroso, Inês | Tuomilehto, Jaakko | Boehnke, Michael | Florez, Jose C | Hamsten, Anders | Watkins, Hugh | Njølstad, Inger | Wichmann, H-Erich | Caulfield, Mark J | Khaw, Kay-Tee | van Duijn, Cornelia M | Hofman, Albert | Wareham, Nicholas J | Langenberg, Claudia | Whitfield, John B | Martin, Nicholas G | Montgomery, Grant | Scapoli, Chiara | Tzoulaki, Ioanna | Elliott, Paul | Thorsteinsdottir, Unnur | Stefansson, Kari | Brittain, Evan L | McCarthy, Mark I | Froguel, Philippe | Sexton, Patrick M | Wootten, Denise | Groop, Leif | Dupuis, Josée | Meigs, James B | Deganutti, Giuseppe | Demirkan, Ayse | Pers, Tune H | Reynolds, Christopher A | Aulchenko, Yurii S | Kaakinen, Marika A | Jones, Ben | and, Inga Prokopenko
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1448–1461, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@article{pmid37679419,
title = {GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification},
author = {Vasiliki Lagou and Longda Jiang and Anna Ulrich and Liudmila Zudina and Karla Sofia Gutiérrez González and Zhanna Balkhiyarova and Alessia Faggian and Jared G Maina and Shiqian Chen and Petar V Todorov and Sodbo Sharapov and Alessia David and Letizia Marullo and Reedik Mägi and Roxana-Maria Rujan and Emma Ahlqvist and Gudmar Thorleifsson and Ηe Gao and Εvangelos Εvangelou and Beben Benyamin and Robert A Scott and Aaron Isaacs and Jing Hua Zhao and Sara M Willems and Toby Johnson and Christian Gieger and Harald Grallert and Christa Meisinger and Martina Müller-Nurasyid and Rona J Strawbridge and Anuj Goel and Denis Rybin and Eva Albrecht and Anne U Jackson and Heather M Stringham and Ivan R Corrêa and Eric Farber-Eger and Valgerdur Steinthorsdottir and André G Uitterlinden and Patricia B Munroe and Morris J Brown and Julian Schmidberger and Oddgeir Holmen and Barbara Thorand and Kristian Hveem and Tom Wilsgaard and Karen L Mohlke and Zhe Wang and and Aleksey Shmeliov and Marcel den Hoed and Ruth J F Loos and Wolfgang Kratzer and Mark Haenle and Wolfgang Koenig and Bernhard O Boehm and Tricia M Tan and Alejandra Tomas and Victoria Salem and Inês Barroso and Jaakko Tuomilehto and Michael Boehnke and Jose C Florez and Anders Hamsten and Hugh Watkins and Inger Njølstad and H-Erich Wichmann and Mark J Caulfield and Kay-Tee Khaw and Cornelia M van Duijn and Albert Hofman and Nicholas J Wareham and Claudia Langenberg and John B Whitfield and Nicholas G Martin and Grant Montgomery and Chiara Scapoli and Ioanna Tzoulaki and Paul Elliott and Unnur Thorsteinsdottir and Kari Stefansson and Evan L Brittain and Mark I McCarthy and Philippe Froguel and Patrick M Sexton and Denise Wootten and Leif Groop and Josée Dupuis and James B Meigs and Giuseppe Deganutti and Ayse Demirkan and Tune H Pers and Christopher A Reynolds and Yurii S Aulchenko and Marika A Kaakinen and Ben Jones and Inga Prokopenko and },
doi = {10.1038/s41588-023-01462-3},
issn = {1546-1718},
year = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1448--1461},
abstract = {Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Uddin, Md Mesbah | Saadatagah, Seyedmohammad | Niroula, Abhishek | Yu, Bing | Hornsby, Whitney | Ganesh, Shriienidhie | Lannery, Kim | Shuermans, Art | Honigberg, Michael C | Bick, Alexander G | Libby, Peter | Ebert, Benjamin L | Ballantyne, Christie M | Natarajan, Pradeep
Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis Miscellaneous
2023.
Abstract | Links | BibTeX | Tags:
@misc{pmid37732181,
title = {Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis},
author = {Md Mesbah Uddin and Seyedmohammad Saadatagah and Abhishek Niroula and Bing Yu and Whitney Hornsby and Shriienidhie Ganesh and Kim Lannery and Art Shuermans and Michael C Honigberg and Alexander G Bick and Peter Libby and Benjamin L Ebert and Christie M Ballantyne and Pradeep Natarajan},
doi = {10.1101/2023.09.05.23295093},
year = {2023},
date = {2023-09-01},
journal = {medRxiv},
abstract = {Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.
Bruffaerts, Ronny | Axinn, William G | Ghimire, Dirgha J | Benjet, Corina | Chardoul, Stephanie | Scott, Kate M | Kessler, Ronald C | Schulz, Paul | Smoller, Jordan W
Community exposure to armed conflict and subsequent onset of alcohol use disorder Journal Article
In: Addiction, 2023, ISSN: 1360-0443.
Abstract | Links | BibTeX | Tags:
@article{pmid37755324,
title = {Community exposure to armed conflict and subsequent onset of alcohol use disorder},
author = {Ronny Bruffaerts and William G Axinn and Dirgha J Ghimire and Corina Benjet and Stephanie Chardoul and Kate M Scott and Ronald C Kessler and Paul Schulz and Jordan W Smoller},
doi = {10.1111/add.16343},
issn = {1360-0443},
year = {2023},
date = {2023-09-01},
journal = {Addiction},
abstract = {AIMS: To measure the independent consequences of community-level armed conflict beatings on alcohol use disorders (AUD) among males in Nepal during and after the 2000-2006 conflict.nnDESIGN: A population-representative panel study from Nepal, with precise measures of community-level violent events and subsequent individual-level AUD in males. Females were not included because of low AUD prevalence.nnSETTING: Chitwan, Nepal.nnPARTICIPANTS: Four thousand eight hundred seventy-six males from 151 neighborhoods, systematically selected and representative of Western Chitwan. All residents aged 15-59 were eligible (response rate 93%).nnMEASUREMENTS: Measures of beatings in the community during the conflict (2000-2006), including the date and distance away, were gathered through neighborhood reports, geo-location and official resources, then linked to respondents' life histories of AUD (collected in 2016-2018) using the Nepal-specific Composite International Diagnostic Interview with life history calendar. Beatings nearby predict the subsequent onset of AUD during and after the armed conflict. Data were analyzed in 2021-2022.nnFINDINGS: Cohort-specific, discrete-time models revealed that within the youngest cohort (born 1992-2001), those living in neighborhoods where armed conflict beatings occurred were more likely to develop AUD compared with those in other neighborhoods (odds ratio = 1.66; 95% confidence interval = 1.02-2.71). In this cohort, a multilevel matching analysis designed to simulate a randomized trial showed the post-conflict incidence of AUD for those living in neighborhoods with any armed conflict beatings was 9.5% compared with 5.3% in the matched sample with no beatings.nnCONCLUSIONS: Among male children living in Chitwan, Nepal during the 2000-2006 armed conflict, living in a neighborhood where armed conflict beatings occurred is associated with increased odds of developing subsequent alcohol use disorder. This association was independent of personal exposure to beatings and other mental disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
AIMS: To measure the independent consequences of community-level armed conflict beatings on alcohol use disorders (AUD) among males in Nepal during and after the 2000-2006 conflict.nnDESIGN: A population-representative panel study from Nepal, with precise measures of community-level violent events and subsequent individual-level AUD in males. Females were not included because of low AUD prevalence.nnSETTING: Chitwan, Nepal.nnPARTICIPANTS: Four thousand eight hundred seventy-six males from 151 neighborhoods, systematically selected and representative of Western Chitwan. All residents aged 15-59 were eligible (response rate 93%).nnMEASUREMENTS: Measures of beatings in the community during the conflict (2000-2006), including the date and distance away, were gathered through neighborhood reports, geo-location and official resources, then linked to respondents' life histories of AUD (collected in 2016-2018) using the Nepal-specific Composite International Diagnostic Interview with life history calendar. Beatings nearby predict the subsequent onset of AUD during and after the armed conflict. Data were analyzed in 2021-2022.nnFINDINGS: Cohort-specific, discrete-time models revealed that within the youngest cohort (born 1992-2001), those living in neighborhoods where armed conflict beatings occurred were more likely to develop AUD compared with those in other neighborhoods (odds ratio = 1.66; 95% confidence interval = 1.02-2.71). In this cohort, a multilevel matching analysis designed to simulate a randomized trial showed the post-conflict incidence of AUD for those living in neighborhoods with any armed conflict beatings was 9.5% compared with 5.3% in the matched sample with no beatings.nnCONCLUSIONS: Among male children living in Chitwan, Nepal during the 2000-2006 armed conflict, living in a neighborhood where armed conflict beatings occurred is associated with increased odds of developing subsequent alcohol use disorder. This association was independent of personal exposure to beatings and other mental disorders.
Gao, Han | Liu, Ruize | Huang, Hailiang | Liu, Zhanju
Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine Journal Article
In: Clin Transl Med, vol. 13, no. 9, pp. e1404, 2023, ISSN: 2001-1326.
@article{pmid37658615,
title = {Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine},
author = {Han Gao and Ruize Liu and Hailiang Huang and Zhanju Liu},
doi = {10.1002/ctm2.1404},
issn = {2001-1326},
year = {2023},
date = {2023-09-01},
journal = {Clin Transl Med},
volume = {13},
number = {9},
pages = {e1404},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cho, So Mi Jemma | Koyama, Satoshi | Honigberg, Michael C | Surakka, Ida | Haidermota, Sara | Ganesh, Shriienidhie | Patel, Aniruddh P | Bhattacharya, Romit | Lee, Hokyou | Kim, Hyeon Chang | Natarajan, Pradeep
Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study Journal Article
In: Eur Heart J, vol. 44, no. 36, pp. 3456–3465, 2023, ISSN: 1522-9645.
Abstract | Links | BibTeX | Tags:
@article{pmid37350734,
title = {Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study},
author = {So Mi Jemma Cho and Satoshi Koyama and Michael C Honigberg and Ida Surakka and Sara Haidermota and Shriienidhie Ganesh and Aniruddh P Patel and Romit Bhattacharya and Hokyou Lee and Hyeon Chang Kim and Pradeep Natarajan},
doi = {10.1093/eurheartj/ehad380},
issn = {1522-9645},
year = {2023},
date = {2023-09-01},
journal = {Eur Heart J},
volume = {44},
number = {36},
pages = {3456--3465},
abstract = {AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence.nnMETHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686).nnCONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence.nnMETHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686).nnCONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.
Kitano, Rie | Madan, Neel | Mikami, Takahisa | Madankumar, Rajeevi | Skotko, Brian G | Santoro, Stephanie | Ralston, Steven J | Bianchi, Diana W | Tarui, Tomo
Biometric magnetic resonance imaging analysis of fetal brain development in down syndrome Journal Article
In: Prenat Diagn, 2023, ISSN: 1097-0223.
Abstract | Links | BibTeX | Tags:
@article{pmid37698481,
title = {Biometric magnetic resonance imaging analysis of fetal brain development in down syndrome},
author = {Rie Kitano and Neel Madan and Takahisa Mikami and Rajeevi Madankumar and Brian G Skotko and Stephanie Santoro and Steven J Ralston and Diana W Bianchi and Tomo Tarui},
doi = {10.1002/pd.6436},
issn = {1097-0223},
year = {2023},
date = {2023-09-01},
journal = {Prenat Diagn},
abstract = {OBJECTIVES: To assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI).nnMETHODS: We scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images.nnRESULTS: In the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls.nnCONCLUSIONS: The study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVES: To assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI).nnMETHODS: We scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images.nnRESULTS: In the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls.nnCONCLUSIONS: The study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls.
Nowbandegani, Pouria Salehi | Wohns, Anthony Wilder | Ballard, Jenna L | Lander, Eric S | Bloemendal, Alex | Neale, Benjamin M | O'Connor, Luke J
Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies Journal Article
In: Nat Genet, vol. 55, no. 9, pp. 1494–1502, 2023, ISSN: 1546-1718.
Abstract | Links | BibTeX | Tags:
@article{pmid37640881,
title = {Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies},
author = {Pouria Salehi Nowbandegani and Anthony Wilder Wohns and Jenna L Ballard and Eric S Lander and Alex Bloemendal and Benjamin M Neale and Luke J O'Connor},
doi = {10.1038/s41588-023-01487-8},
issn = {1546-1718},
year = {2023},
date = {2023-09-01},
journal = {Nat Genet},
volume = {55},
number = {9},
pages = {1494--1502},
abstract = {Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using large correlation matrices, but this approach is inefficient, especially in ancestrally diverse studies. In the present study, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We published LDGMs and ancestry-specific LDGM precision matrices for 18 million common variants (minor allele frequency >1%) in five ancestry groups, validated their accuracy and demonstrated order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implemented an extremely fast multiancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally diverse genetic association data across millions of variants and individuals.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using large correlation matrices, but this approach is inefficient, especially in ancestrally diverse studies. In the present study, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We published LDGMs and ancestry-specific LDGM precision matrices for 18 million common variants (minor allele frequency >1%) in five ancestry groups, validated their accuracy and demonstrated order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implemented an extremely fast multiancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally diverse genetic association data across millions of variants and individuals.
van Essen, Thomas A | van Erp, Inge A M | Lingsma, Hester F | Pisică, Dana | Yue, John K | Singh, Ranjit D | van Dijck, Jeroen T J M | Volovici, Victor | Younsi, Alexander | Kolias, Angelos | Peppel, Lianne D | Heijenbrok-Kal, Majanka | Ribbers, Gerard M | Menon, David K | Hutchinson, Peter J A | Manley, Geoffrey T | Depreitere, Bart | Steyerberg, Ewout W | Maas, Andrew I R | de Ruiter, Godard C W | and, Wilco C Peul
In: EClinicalMedicine, vol. 63, pp. 102161, 2023, ISSN: 2589-5370.
Abstract | Links | BibTeX | Tags:
@article{pmid37600483,
title = {Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study},
author = {Thomas A van Essen and Inge A M van Erp and Hester F Lingsma and Dana Pisică and John K Yue and Ranjit D Singh and Jeroen T J M van Dijck and Victor Volovici and Alexander Younsi and Angelos Kolias and Lianne D Peppel and Majanka Heijenbrok-Kal and Gerard M Ribbers and David K Menon and Peter J A Hutchinson and Geoffrey T Manley and Bart Depreitere and Ewout W Steyerberg and Andrew I R Maas and Godard C W de Ruiter and Wilco C Peul and },
doi = {10.1016/j.eclinm.2023.102161},
issn = {2589-5370},
year = {2023},
date = {2023-09-01},
journal = {EClinicalMedicine},
volume = {63},
pages = {102161},
abstract = {BACKGROUND: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy.nnMETHODS: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582).nnFINDINGS: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]).nnINTERPRETATION: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling.nnFUNDING: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy.nnMETHODS: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582).nnFINDINGS: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]).nnINTERPRETATION: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling.nnFUNDING: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.
Benson, Mark D | Eisman, Aaron S | Tahir, Usman A | Katz, Daniel H | Deng, Shuliang | Ngo, Debby | Robbins, Jeremy M | Hofmann, Alissa | Shi, Xu | Zheng, Shuning | Keyes, Michelle | Yu, Zhi | Gao, Yan | Farrell, Laurie | Shen, Dongxiao | Chen, Zsu-Zsu | Cruz, Daniel E | Sims, Mario | Correa, Adolfo | Tracy, Russell P | Durda, Peter | Taylor, Kent D | Liu, Yongmei | Johnson, W Craig | Guo, Xiuqing | Yao, Jie | Chen, Yii-Der Ida | Manichaikul, Ani W | Jain, Deepti | Yang, Qiong | | Bouchard, Claude | Sarzynski, Mark A | Rich, Stephen S | Rotter, Jerome I | Wang, Thomas J | Wilson, James G | Clish, Clary B | Sarkar, Indra Neil | Natarajan, Pradeep | Gerszten, Robert E
Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma Journal Article
In: Cell Metab, vol. 35, no. 9, pp. 1646–1660.e3, 2023, ISSN: 1932-7420.
Abstract | Links | BibTeX | Tags:
@article{pmid37582364,
title = {Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma},
author = {Mark D Benson and Aaron S Eisman and Usman A Tahir and Daniel H Katz and Shuliang Deng and Debby Ngo and Jeremy M Robbins and Alissa Hofmann and Xu Shi and Shuning Zheng and Michelle Keyes and Zhi Yu and Yan Gao and Laurie Farrell and Dongxiao Shen and Zsu-Zsu Chen and Daniel E Cruz and Mario Sims and Adolfo Correa and Russell P Tracy and Peter Durda and Kent D Taylor and Yongmei Liu and W Craig Johnson and Xiuqing Guo and Jie Yao and Yii-Der Ida Chen and Ani W Manichaikul and Deepti Jain and Qiong Yang and and Claude Bouchard and Mark A Sarzynski and Stephen S Rich and Jerome I Rotter and Thomas J Wang and James G Wilson and Clary B Clish and Indra Neil Sarkar and Pradeep Natarajan and Robert E Gerszten},
doi = {10.1016/j.cmet.2023.07.012},
issn = {1932-7420},
year = {2023},
date = {2023-09-01},
journal = {Cell Metab},
volume = {35},
number = {9},
pages = {1646--1660.e3},
abstract = {Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.
The Center for Genomic Medicine (CGM) comprises one of the largest and most vibrant hubs of genomic medicine research in the world. The CGM includes 46 faculty collaborating to define the ‘genomic medicine cycle’ – which envisages a genomics community seeking to advance research from basic genomics research to ultimately using genome information for diagnostics and targeted therapeutics. All of our investigators are faculty at Harvard Medical School, and many members of our community are also investigators at the Broad Institute of Harvard and MIT.
