Time filter

Source Type

Corbeil-Essonnes, France

Marquez M.,French National Center for Scientific Research | Huyvaert M.,French National Center for Scientific Research | Perry J.R.B.,University of Oxford | Perry J.R.B.,University of Exeter | And 22 more authors.
Diabetes | Year: 2012

It has recently been suggested that the low-frequency c.136-14-136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14-136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14-136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease. © 2012 by the American Diabetes Association. Source

Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,Lille University | Bonnefond A.,European Genomic Institute for Diabetes EGID | Skrobek B.,French National Center for Scientific Research | And 28 more authors.
Nature Genetics | Year: 2013

Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging and to predict cancer. Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease and is associated with higher prevalence of cancers. Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10 -5) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10 -5). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10 -4). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years (P = 8.60 × 10 -3). In conclusion, given the increased risk of cancer in CME carriers, our results may have profound clinical implications in patients with severe T2D. © 2013 Nature America, Inc. All rights reserved. Source

Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,University of Lille Nord de France | Clement N.,French Institute of Health and Medical Research | Clement N.,University of Paris Descartes | And 44 more authors.
Nature Genetics | Year: 2012

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT 2) increase type 2 diabetes (T2D) risk. Although the strongest association signal was highly significant (P < 1 - 10 g 20), its contribution to T2D risk was modest (odds ratio (OR) of g1/41.10g1.15). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78g6.18; P = 1.64 - 10 g 4). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17g14.82; P = 4.09 - 10 g4). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49g10.07; P = 5.37 - 10 g 3). This study establishes a firm functional link between MTNR1B and T2D risk. © 2012 Nature America, Inc. All rights reserved. Source

Robiou-Du-Pont S.,French National Center for Scientific Research | Robiou-Du-Pont S.,University of Lille Nord de France | Bonnefond A.,University Paris Diderot | Yengo L.,French National Center for Scientific Research | And 18 more authors.
International Journal of Obesity | Year: 2013

Context: Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear.Objective: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and β-cell dysfunction, and on T2D risk.Design:We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic β-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). Results: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (β=0.02; P-value=7.16 × 10-9 for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased β-cell function (β=0.01; P-value=1.05 × 10-6 and β=0.04; P-value=3.45 × 10-4, respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 × 10-3 and OR=1.15; P-value=9.46 × 10-4, respectively). Adjustment for BMI abolished all significant associations. Conclusions: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased β-cell function, and weakly increases the T2D risk. These associations are mediated by BMI. © 2013 Macmillan Publishers Limited. Source

Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,University of Lille Nord de France | Yengo L.,French National Center for Scientific Research | Yengo L.,University of Lille Nord de France | And 31 more authors.
Diabetologia | Year: 2013

Aims/hypothesis: MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. Methods: BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. Results: No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. Conclusions/interpretation: No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation. © 2012 Springer-Verlag Berlin Heidelberg. Source

Discover hidden collaborations