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 d