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The PPARG Pro12Ala Polymorphism Is Associated With a Decreased Risk of Developing Hyperglycemia Over 6 Years and Combines With the Effect of the APM1 G-11391A Single Nucleotide Polymorphism

The Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) Study

¹ Institut National de la Santé et de la Recherche Médicale (INSERM) U695, Déterminants Génétiques du Diabète de Type 2 et de ses Complications Cardiovasculaires, Faculté Xavier Bichat, Paris, France
² Université Paris 7 Denis Diderot, Paris, France
³ Centre National de Recherche (CNRS), Unité Mixte de Recherche (UMR) 8090, Institut de Biologie de Lille, Institut Pasteur, Lille, France
⁴ Institut Régional Pour la Santé, Tours, France
⁵ INSERM, U258-IFR69, Villejuif, France
⁶ Imperial College Genome Centre and Genomic Medicine, Imperial College, London, U.K
⁷ Service d’Endocrinologie, Diabétologie, Nutrition, Groupe Hospitalier Bichat Claude Bernard, Assistance Public-Hôpitaux de Paris (AP-HP), Paris, France

Address correspondence and reprint requests to Frédéric Fumeron, INSERM, U695, Xavier Bichat Medical School, BP 416, 16 rue Henri Huchard, 75870 Paris Cedex 18, France. E-mail: fumeron{at}bichat.inserm.fr

Abbreviations: DESIR, Data From an Epidemiological Study on the Insulin Resistance Syndrome; HOMA-IR, homeostasis model assessment of insulin resistance; IFG, impaired fasting glucose; PPAR, peroxisome proliferator–activated receptor; SNP, single nucleotide polymorphism

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.

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