828 results found
Khamis A, Ning L, Balkau B, et al., 2022, Epigenetic changes associated with hyperglycaemia exposure in the longitudinal D.E.S.I.R. cohort., Diabetes Metab, Vol: 48
AIM: - Understanding DNA methylation dynamics associated with progressive hyperglycaemia exposure could provide early diagnostic biomarkers and an avenue for delaying type 2 diabetes mellitus (T2DM). We aimed to identify DNA methylation changes during a 6-year period associated with early hyperglycaemia exposure using the longitudinal D.E.S.I.R. COHORT: METHODS: - We selected individuals with progressive hyperglycaemia exposure based on T2DM diagnostic criteria: 27 with long-term exposure, 34 with short-term exposure and 34 normoglycaemic controls. DNA from blood at inclusion and at the 6-year visit was subjected to methylation analysis using 850K methylation-EPIC arrays. A linear mixed model was used to perform an epigenome-wide association study (EWAS) and identify methylated changes associated with hyperglycaemia exposure during a 6-year time-period. RESULTS: - We did not identify differentially methylated sites that reached false discovery rate (FDR)-significance in our cohort. Based on EWAS, we focused our analysis on methylation sites that had a constant effect during the 6 years across the hyperglycaemia groups compared to controls and found the most statistically significant site was the reported cg19693031 probe (TXNIP). We also performed an EWAS with HbA1c, using the inclusion and the 6-year methylation data and did not identify any FDR-significant CpGs. CONCLUSIONS: - Our study reveals that DNA methylation changes are not robustly associated with hyperglycaemia exposure or HbA1c during a short-term period, however, our top loci indicate potential interest and should be replicated in larger cohorts.
Lemaitre M, Douillard C, Froguel P, et al., 2022, Management of pregnancy in a patient with congenital hyperinsulinism treated with association of diazoxide/calcium channel blocker, ACTA DIABETOLOGICA, Vol: 59, Pages: 1117-1120, ISSN: 0940-5429
Saeed S, Janjua QM, Haseeb A, et al., 2022, Rare Variant Analysis of Obesity-Associated Genes in Young Adults With Severe Obesity From a Consanguineous Population of Pakistan., Diabetes, Vol: 71, Pages: 694-705
Recent advances in genetic analysis have significantly helped in progressively attenuating the heritability gap of obesity and have brought into focus monogenic variants that disrupt the melanocortin signaling. In a previous study, next-generation sequencing revealed a monogenic etiology in ∼50% of the children with severe obesity from a consanguineous population in Pakistan. Here we assess rare variants in obesity-causing genes in young adults with severe obesity from the same region. Genomic DNA from 126 randomly selected young adult obese subjects (BMI 37.2 ± 0.3 kg/m2; age 18.4 ± 0.3 years) was screened by conventional or augmented whole-exome analysis for point mutations and copy number variants (CNVs). Leptin, insulin, and cortisol levels were measured by ELISA. We identified 13 subjects carrying 13 different pathogenic or likely pathogenic variants in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1, and SIM1. We also identified for the first time in the human, two homozygous stop-gain mutations in ASNSD1 and IFI16 genes. Inactivation of these genes in mouse models has been shown to result in obesity. Additionally, we describe nine homozygous mutations (seven missense, one stop-gain, and one stop-loss) and four copy-loss CNVs in genes or genomic regions previously linked to obesity-associated traits by genome-wide association studies. Unexpectedly, in contrast to obese children, pathogenic mutations in LEP and LEPR were either absent or rare in this cohort of young adults. High morbidity and mortality risks and social disadvantage of children with LEP or LEPR deficiency may in part explain this difference between the two cohorts.
Tobi EW, Juvinao-Quintero DL, Ronkainen J, et al., 2022, Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies., Diabetes Care, Vol: 45, Pages: 614-623
OBJECTIVE: Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS: To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS: Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] -0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS: Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.
Le Collen L, Delemer B, Spodenkiewicz M, et al., 2022, Compound genetic etiology in a patient with a syndrome including diabetes, intellectual deficiency and distichiasis, ORPHANET JOURNAL OF RARE DISEASES, Vol: 17
Thamtarana PJ, Marucci A, Pannone L, et al., 2021, Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 107, Pages: 668-684, ISSN: 0021-972X
Meulebrouck S, Queniat G, Baron M, et al., 2021, Mirror effects of rare OPRD1 variants on the aetiology of type 2 diabetes and obesity, Publisher: SPRINGER, Pages: 109-109, ISSN: 0012-186X
Khamis A, Canouil M, Keikkala E, et al., 2021, Both gestational diabetes exposure and maternal methylome interaction impacts offspring epigenetic signature, Publisher: SPRINGER, Pages: 143-144, ISSN: 0012-186X
Slieker RC, Donnelly LA, Lopez-Noriega L, et al., 2021, Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study, Publisher: SPRINGER, Pages: 108-108, ISSN: 0012-186X
Canouil M, Khamis A, Keikkala E, et al., 2021, Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome, DIABETES CARE, Vol: 44, Pages: 1992-1999, ISSN: 0149-5992
Hegron A, Huh E, Deupi X, et al., 2021, Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants, ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, Vol: 4, Pages: 1614-1627
De T, Goncalves A, Speed D, et al., 2021, Signatures of TSPAN8 variants associated with human metabolic regulation and diseases, ISCIENCE, Vol: 24
Voisin S, Jacques M, Landen S, et al., 2021, Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle, JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, Vol: 12, Pages: 1064-1078, ISSN: 2190-5991
Chen J, Spracklen CN, Marenne G, et al., 2021, The trans-ancestral genomic architecture of glycemic traits, Nature Genetics, Vol: 53, Pages: 840-860, ISSN: 1061-4036
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10−8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
Paccoud R, Saint-Laurent C, Piccolo E, et al., 2021, SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations, SCIENCE TRANSLATIONAL MEDICINE, Vol: 13, ISSN: 1946-6234
Porcu E, Gilardi F, Darrous L, et al., 2021, Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322
Hu M, Cebola I, Carrat G, et al., 2021, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion., Cell Research, Vol: 34, Pages: 1-1, ISSN: 1001-0602
Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.
Lagou V, Mägi R, Hottenga J-J, et al., 2021, Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability., Nat Commun, Vol: 12
Bonnefond A, Froguel P, 2021, Clustering for a better prediction of type 2 diabetes mellitus, NATURE REVIEWS ENDOCRINOLOGY, Vol: 17, Pages: 193-194, ISSN: 1759-5029
Lagou V, Maegi R, Hottenga J-J, et al., 2021, Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability, NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723
Vaxillaire M, Bonnefond A, Liatis S, et al., 2021, Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries, DIABETES RESEARCH AND CLINICAL PRACTICE, Vol: 171, ISSN: 0168-8227
Saeed S, Arslan M, Manzoor J, et al., 2020, Genetic aetiology of early onset severe obesity revealed in half of the affected cases from a consanguineous population of Pakistan, Publisher: SPRINGERNATURE, Pages: 568-569, ISSN: 1018-4813
Vaxillaire M, Bonnefond A, Liatis S, et al., 2020, Monogenic diabetes gene screening in a transnational multicenter study from eleven countries of the Mediterranean area, Publisher: SPRINGERNATURE, Pages: 683-684, ISSN: 1018-4813
Marselli L, Piron A, Suleiman M, et al., 2020, Persistent or transient human β cell dysfunction induced by metabolic stress: specific signatures and shared gene expression with type 2 diabetes, Cell Reports, Vol: 33, ISSN: 2211-1247
Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.
Bar N, Korem T, Weissbrod O, et al., 2020, A reference map of potential determinants for the human serum metabolome, NATURE, Vol: 588, Pages: 135-140, ISSN: 0028-0836
El Shamieh S, Stathopoulou MG, Bonnefond A, et al., 2020, Obesity status modifies the association between rs7556897T > C in the intergenic region SLC19A3-CCL20 and blood pressure in French children, CLINICAL CHEMISTRY AND LABORATORY MEDICINE, Vol: 58, Pages: 1819-1827, ISSN: 1434-6621
Imam A, Winnebeck EC, Buchholz N, et al., 2020, Circadian, Sleep and Caloric Intake Phenotyping in Type 2 Diabetes Patients With Rare Melatonin Receptor 2 Mutations and Controls: A Pilot Study, FRONTIERS IN PHYSIOLOGY, Vol: 11, ISSN: 1664-042X
Baron M, Froguel P, Bonnefond A, 2020, Something new in the genetics of monogenic obesity and its insights into pathophysiology, M S-MEDECINE SCIENCES, Vol: 36, Pages: 859-865, ISSN: 0767-0974
Bonnefond A, Boissel M, Bolze A, et al., 2020, Pathogenic variants in actionable MODY genes are associated with type 2 diabetes, NATURE METABOLISM, Vol: 2, Pages: 1126-+
Vogelezang S, Bradfield JP, Ahluwalia TS, et al., 2020, Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits, PLoS Genetics, Vol: 16, Pages: 1-26, ISSN: 1553-7390
The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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