Single nucleotide polymorphisms of the peroxisome proliferator-activated receptor-alpha gene (PPARA) influence the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial.

Abstract

Peroxisome proliferator-activated receptor (PPAR) alpha, a transcriptionfactor of the nuclear receptor superfamily, regulates fatty acidoxidation. We evaluated the association of single nucleotide polymorphisms(SNPs) of the PPAR-alpha gene (PPARA) with the conversion from impairedglucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDMtrial in order to investigate the effect of acarbose in comparisonwith placebo on the prevention of diabetes. In the placebo group,the G (162V) allele of rs1800206 increased the risk for diabetesby 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levelsof plasma glucose and insulin. The effect of this allele on the riskof diabetes in the placebo group was enhanced by the simultaneouspresence of the risk alleles of the PPAR-gamma2, PPAR-gamma coactivator1alpha, and hepatic nuclear factor 4alpha genes (odds ratios 2.2,2.5, and 3.4, respectively). In the acarbose group, subjects carryingthe minor G allele of rs4253776 and the CC genotype of rs4253778of PPARA had a 1.7- and 2.7-fold increased risk for diabetes. Ourdata indicate that SNPs of PPARA increase the risk of type 2 diabetesalone and in combination with the SNPs of other genes acting closelywith PPAR-alpha.