Abstract
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. 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). 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 x 10(-5)) and decreased homeostasis model assessment of beta-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 x 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 x 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. 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.
Highlights
The GCK (Glucokinase) Ϫ30A allele was associated with increased type 2 diabetes risk at the end of the follow-up study under an additive model, as supported in independent French diabetic case subjects, with increased fasting glycemia (0.85% per A allele, P ϭ 6 ϫ 10Ϫ5) and decreased homeostasis model assessment of -cell function (4%, P ϭ 0.0009)
The T allele of the noncoding rs7903146 variant in TCF7L2 was shown to be associated with an increased incidence of hyperglycemia in the French DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) prospective study [38]. In this population-based sample with a longitudinal follow-up of 9 years, we evaluated the contribution to type 2 diabetes risk at the end of the study and to diabetes incidence of 19 common single nucleotide polymorphism (SNP), some of which were reproducibly associated with type 2 diabetes in case-control designs (Table 1)
4,466 samples with two previously reported European studies from Denmark [13] and Germany [14] (P for heterogeneity ϭ 0.72), we found a very significant association between the GCK (Ϫ30) A allele and diabetes, with an overall odds ratio (OR) of 1.22 (Padditive ϭ 10Ϫ6; after adjustment for age and sex using the Mantel-Haenszel analysis of fixed effects)
Summary
Table 1), are in concordance with those previously reported in subjects of European ancestry, and all genotype groups were in Hardy-Weinberg equilibrium (P Ͼ 0.05). Using Cox proportional hazards models, the GCK Ϫ30A allele was shown to be significant for diabetes incidence (HR 1.34 [95% CI 1.04 –1.74], Padditive ϭ 0.03, and 2.39 [1.30 – 4.42] for the AA genotype, Precessive ϭ 0.005) and hyperglycemia (both IFG and diabetic case subjects) with an HR of 1.26 and 2.17 under additive and recessive models, respectively (P Յ 0.005) (Table 3). Both KCNJ11E23K and IL6 Ϫ174G/C SNPs were associated with risk of type 2 diabetes (Padditive Ͻ 0.01, Table 3). KCNJ11-E23K, TCF7L2, and PPARG-P12A, already shown to have a combined effect on type 2 diabetes prevalence [45], provided an OR of 1.27 (95% CI 1.11–1.45) (P ϭ 4 ϫ 10Ϫ4) by each additional risk allele
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
