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Objective: Uncoupling protein 2 (UCP2) is a physiological downregulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (-866G>A) modulates mRNA expression, with increased expression associated with the A allele. We investigated association of this variant with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects. Research Design and Methods: We studied 3,122 subjects from the 6-year prospective Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD incidence at follow-up). An independent, hospital-based cohort of 335 men, 52% of whom had CAD, was also studied. Results: We observed an inverse association of the A allele with incident cases of CAD in a dominant model (hazard risk 0.88 [95% CI 0.80-0.96]; P = 0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, whereas no association was observed in women. All CAD phenotypes considered--myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), and sudden death--contributed significantly to the association. Results were replicated in a cross-sectional study of an independent cohort (odds ratio 0.47 [95% CI 0.25-0.89]; P = 0.02 for a recessive model). Conclusions: The A allele of the -866G>A variant of UCP2 was associated with reduced risk of CAD in men with type 2 diabetes in a 6-year prospective study. Decreased risk of myocardial infarction, angina pectoris, CABG, and sudden death contributed individually and significantly to the reduction of CAD risk. This association was independent of other common CAD risk factors. [ABSTRACT FROM AUTHOR]

Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44-0.99], P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44-0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D' = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOMA-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested. Diabetes 55: 1157-1162, 2006 [ABSTRACT FROM AUTHOR]

The emerging picture of type 2 diabetes (T2D) genetics involves differently assembled gene variants, each modestly increasing or decreasing risk with environmental exposure. The relevance of these genes for disease prediction in general populations has not been extensively tested so far. From a 9-year prospective study of a middle-aged Caucasian cohort, 19 common polymorphisms in 15 well known candidate genes were analyzed for their contribution to both prevalence and incidence to glucose intolerance in 4,119 participants (including 695 (.16.9%) hyperglycemic and 326 (7.9%) T2D subjects at the end of the study, with 182 (5%) incident diabetic cases). The GCK (Glucokinase)-30A allele is associated with increased T2D risk (adjusted OR 1.35 [1.09-1.69] under an additive model), increased fasting glycemia (p=2.10-5), decreased HOMA-B (p=4.10-4), a result further supported in an independent T2D French cohort (OR 1.20 [1.05-1.36], p = 0.006). IL6 (Interleukine 6)-174 G/C, IL6R(IL6 receptor)-D358A and also SREBF1-G952G might interact with age in the risk of T2D (p 56 years (p < 0.05). Five polymorphisms predict new T2D cases in the D.E.S.I.R. cohort: GCK-30G/A (HR 1.36 [1.05-1.76] per supplementary A-allele), KCNJ11 (KIR6.2)-E23K (HR 1.43 [1.14-1.78] per K-allele), TCF7L2-rs7903146 (HR 1.48 [1.10-1.99] per T-allele), whereas IL6-174G/C and IL6R-D358A decrease risk (HR 0.51-0.63 [0.31-0.99]). Our data are consistent with an allelic multigenic multiplicative model: each additional risk allele at GCK, TCF7L2 and IL6 loci (i.e. best model) increased T2D risk by 1.33 [1.18-1.49] (p = 3.10-6), with an OR of 4.9 [2.05-11.7] in carriers of at least 4 at-risk alleles. Genome-wide association studies have very recently identified new diabetes-associated genes; such genetic information will be tested in the D.E.S.I.R study, helping to define individual genetic profiles at higher risk for T2D. [ABSTRACT FROM AUTHOR]