Single Nucleotide Polymorphisms of PPARD in Combination With the Gly482Ser Substitution of PGC-1A and the Pro12Ala Substitution of PPARG2 Predict the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

Abstract

Peroxisome proliferator–activated receptor (PPAR)-δ regulates fatty acid oxidation and improves insulin sensitivity. We screened six single nucleotide polymorphisms (SNPs) of the PPAR-δ gene (PPARD) for an association with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in 769 subjects participating in the STOP-NIDDM trial. A 2.7-fold increase in the risk of diabetes was observed in female carriers of the C allele of rs6902123 (95% CI 1.44–5.30; adjusted P = 0.002). In the placebo group, subjects possessing both the 482Ser allele of the PPAR-γ coactivator-1α gene (PGC-1A) and the rare allele of two SNPs of PPARD (rs6902123 and rs3734254) had up to 2.5-fold increased risk for diabetes. Furthermore, women carrying the C allele of rs6902123 of PPARD and the Pro12Pro genotype of the PPAR-γ2 gene (PPARG2) had a 3.9-fold (95% CI 1.79–8.63; P = 0.001)-higher risk for diabetes than women with protective genotypes. Expression levels of PPAR-δ in subcutaneous adipose tissue of 87 offspring of Finnish patients with type 2 diabetes did not differ among the genotype groups of SNPs of PPARD. We conclude that SNPs in PPARD modify the conversion from IGT to type 2 diabetes, particularly in combination with the SNPs of PGC-1A and PPARG2.