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 DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) 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 [95% CI 1.07–1.69]) under an additive model, as supported in independent French diabetic case subjects (OR 1.22, P = 0.007), with increased fasting glycemia (0.85% per A allele, P = 6 × 10⁻⁵) and decreased homeostasis model assessment of β-cell function (4%, P = 0.0009). IL6 (Interleukin- 6) −174 G/C interacts with age in disease risk and modulates fasting glycemia according to age (1.36% decrease over 56 years, P = 5 × 10⁻⁵). These polymorphisms together with KCNJ11 (Kir6.2)-E23K and TCF7L2-rs7903146 may predict diabetes incidence in the DESIR cohort. Each additional risk allele at GCK, TCF7L2, and IL6 increased risk by 1.34 (P = 2 × 10⁻⁶), with an OR of 2.48 (95% CI 1.59–3.86), in carriers of at least four at-risk alleles compared with those with none or one 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.