Corbeil-Essonnes, France
Corbeil-Essonnes, France

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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 45 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.


Perry J.R.B.,University of Exeter | Perry J.R.B.,University of Oxford | Perry J.R.B.,King's College London | Voight B.F.,The Broad Institute of MIT and Harvard | And 82 more authors.
PLoS Genetics | Year: 2012

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10-9, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3×10-8, OR = 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2×10-14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10-16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes. © 2012 Perry et al.


PubMed | Karolinska Institutet, Instituto Of Ricovero E Cura A Carattere Scientifico Irccs, German Institute of Human Nutrition, Kuopio University Hospital and 60 more.
Type: Comparative Study | Journal: Nature genetics | Year: 2015

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. Credible sets of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.


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 29 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.


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.


Bonnefond A.,University of Lorraine | Bonnefond A.,University Paris Diderot | Saulnier P.-J.,University of Poitiers | Saulnier P.-J.,Clinical investigation Center 0802 | And 34 more authors.
PLoS ONE | Year: 2013

Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits. SNPs were genotyped in several case-control studies: French and Danish T2D studies (Ncases = 6,920-Ncontrols = 3,875 and Ncases = 3,561-Ncontrols = 2,623; respectively), two French studies one for diabetic nephropathy (Ncases = 1,242-Ncontrols = 860) and the other for diabetic retinopathy (Ncases = 1,336-Ncontrols = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions. In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7×10-5). Furthermore, the same allele was associated with higher glycated hemoglobin levels (β = 0.02%; P = 9.2×10-3). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients. In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected. © 2013 Bonnefond et al.


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.


PubMed | University Utrecht, Steno Diabetes Center, Corbeil Essonnes Hospital, EASD 1988 2015 and 5 more.
Type: | Journal: Acta diabetologica | Year: 2016

We used data from the GUIDANCE Study to determine the care of people with type 2 diabetes according to age and accompanying cardiovascular diseases and to assess indicators of overtreatment of glycaemia.The GUIDANCE study was a retrospective, cross-sectional study from 2009-2010 based on the records of 7597 people in France, Belgium, Italy, the Netherlands, Sweden, UK, Ireland and Germany. We analysed the level of metabolic control achieved and blood glucose-lowering medication used in different age groups and in relation to accompanying diseases.4.459 patients (59.1%) were 65years or older. Their HbA1c levels were similar to those with <65years. 44.7% of patients 65years had an HbA1c 7% (53mmol/mol) and were treated with insulin or sulfonylureas, and 27.1% of them had ischaemic heart disease or congestive heart failure. Significantly more patients with heart disease had HbA1c values 7% (53mmol/mol) and were treated more often with insulin or sulfonylureas compared to patients of the same age without heart disease.Most patients were treated according to guidelines valid at the time this large international patient sample was surveyed. Older and younger patients were at a similar level of metabolic control, and almost half of the patients with an age of 65years and treated with insulin or sulfonylurea had HbA1c levels below the target range (7%) for younger patients. However, these patients have an increased risk of severe hypoglycaemic events with potentially dangerous complications, particularly in those with cardiovascular diseases.


Scheen A.J.,University of Liège | Charpentier G.,Corbeil Essonnes Hospital | Ostgren C.J.,Linköping University | Hellqvist A.,Astrazeneca | Gause-Nilsson I.,Astrazeneca
Diabetes/Metabolism Research and Reviews | Year: 2010

Background Dipeptidyl peptidase-4 inhibitors improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other anti-diabetic drugs (metformin, sulphonylurea, or thiazolidinedione). This 18-week, phase 3b, multicentre, double-blind, non- inferiority trial compared the efficacy and safety of two dipeptidyl peptidase-4 inhibitors, saxagliptin and sitagliptin, in patients whose glycaemia was inad- equately controlled with metformin. Methods Adult type 2 diabetes mellitus patients (N = 801) with glycated haemoglobin (HbA1c) 6.5-10% on stable metformin doses (1500-3000 mg/day) were randomized 1: 1 to add-on 5 mg saxagliptin or 100 mg sitagliptin once daily for 18 weeks. The primary efficacy analysis was a comparison of the change from baseline HbA1c at week 18 in per-protocol patients. Noninferiority was concluded if the upper limit of the two-sided 95% confidence interval of the HbA1c difference between treatments was <0.3%. Results The adjusted mean changes in HbA1c following the addition of saxagliptin or sitagliptin to stable metformin therapy were -0.52 and -0.62%, respectively. The between-group difference was 0.09% (95% confidence interval, -0.01 to 0.20%), demonstrating noninferiority. Both treatments were generally well tolerated; incidence and types of adverse events were comparable between groups. Hypoglycaemic events, mostly mild, were reported in approximately 3% of patients in each treatment group. Body weight declined by a mean of 0.4 kg in both groups. Conclusions Saxagliptin added to metformin therapy was effective in improving glycaemic control in patients with type 2 diabetes mellitus in- adequately controlled by metformin alone; saxagliptin plus metformin was noninferior to sitagliptin plus metformin, and was generally well tolerated. © 2010 John Wiley & Sons, Ltd.


Stone M.A.,University of Leicester | Charpentier G.,Corbeil Essonnes Hospital | Doggen K.,Scientific Institute of Public Health | Kuss O.,Martin Luther University of Halle Wittenberg | And 7 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-We sought to determine levels of adherence in eight European countries to recommendations for the management of type 2 diabetes and to investigate factors associated with key intermediate outcomes. RESEARCH DESIGN AND METHODS-GUIDANCE was a cross-sectional study including retrospective data extraction from the medical records of people with type 2 diabetes recruited, using a shared protocol, from primary and specialist care sites in the following eight European countries: Belgium, France, Germany, Italy, Ireland, Sweden, the Netherlands, and the United Kingdom. The dataset for analysis comprised 7,597 cases. Proportions meeting process and outcome criteria were determined, including between-country variations. Logistic regression was used to investigate potential predictors of meeting targets for HbA1c, blood pressure, and LDL cholesterol. RESULTS-In the total sample, adherence to process recommendations was high for some measures, for example, HbA1c recorded in past 12 months in 97.6%of cases. Target achievement for intermediate outcome measures was lower, with only 53.6% having HbA1c < 7%. Considerable between-country variation was identified for both processes and outcomes. The following characteristics were associated with an increased likelihood of meeting targets for all three measures considered (HbA 1c, blood pressure, LDL cholesterol): shorter diagnosis of diabetes; having one or more macrovascular complications; lower BMI; being prescribed lipid-lowering medication; and no current antihypertensive prescribing. CONCLUSIONS-Compared with earlier reports, we have suggested some encouraging positive trends in Europe in relation to meeting targets for the management of people with type 2 diabetes, but there is still scope for further improvement and greater between-country consistency. © 2013 by the American Diabetes Association.

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