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Impact of Common Type 2 Diabetes Risk Polymorphisms in the D.E.S.I.R. Prospective Study

¹ UMR8090 and Institute of Biology, Lille 2 University, CNRS and Pasteur Institute, Lille, France
² Department of Endocrinology-Diabetology, Centre Hospitalier Sud-Francilien, Corbeil-Essonnes, France
³ the Regional Institut for Health, Tours, France
⁴ INSERM U695, Paris, France
⁵ Université Paris Diderot - Paris 7, Paris, France
⁶ Department of Endocrinology-Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France
⁷ INSERM U780-IFR69, Villejuif, France
⁸ University of Paris-Sud, Villejuif, France
⁹ Genomic Medicine, Hammersmith Hospital, Imperial College London, United Kingdom

Objective: The emerging picture of type 2 diabetes genetics involves differently assembled gene variants, each modestly increasing risk with environmental exposure. However, the relevance of these genes for disease prediction has not been extensively tested.

Research Design and Methods: We analyzed 19 common polymorphisms of 14 known candidate genes for their contribution to prevalence and incidence of glucose intolerance in the D.E.S.I.R. prospective study of middle-aged Caucasian subjects, including 3,877 participants (16.8% with hyperglycemia and 7.9% with diabetes after the 9-year study).

Results: The GCK (Glucokinase) -30A allele was associated with increased type 2 diabetes risk at the end of the follow-up study (adjusted OR 1.34 [1.07-1.69] under an additive model, as supported in independent French diabetic cases (OR 1.22, p = 0.007), with increased fasting glycemia (0.85% per A-allele, p = 6.10^-5) and decreased HOMA-B (4%, p = 0.0009). IL6 (Interleukine 6) -174 G/C interacts with age in the disease risk and modulates fasting glycemia according to age (1.36% decrease above 56 years, p = 5.10^-5). These polymorphisms together with KCNJ11(Kir6.2)-E23K and TCF7L2-rs7903146 may predict diabetes incidence in the D.E.S.I.R. cohort. Each additional risk allele at GCK, TCF7L2 and IL6 increased risk by 1.34 (p = 2.10^-6), with OR of 2.48 [1.59-3.86] in carriers of at least 4 at-risk alleles compared to those with 0 or 1 risk allele.

Conclusions: Our data confirm several at-risk polymorphisms for type 2 diabetes in a general population, and demonstrate that prospective studies are valuable designs to complement classical genetic approaches.

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