No abstract

for the STOP-NIDDM Study Group* Peroxisome proliferator-activated receptor (PPAR) ␣, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-␣ gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-␥2, PPAR-␥ coactivator 1␣, and hepatic nuclear factor 4␣ genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7-and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-␣. Diabetes

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.

Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors belonging to the nuclear receptor superfamily. Three isoforms, PPARalpha, PPARgamma, and PPARdelta, which are encoded by separate genes, have been identified. The PPARs act as gene regulators of various metabolic pathways in energy and lipid metabolism, glucose homeostasis, adipogenesis, and inflammation. Two key classes of synthetic compounds, fibrates and thiazolidinediones (glitazones), activate PPARalpha and PPARgamma, respectively. Both of these drugs have several properties that prevent atherosclerosis in the vascular wall and reduce the levels of risk factors for cardiovascular disease. However, clinical trials have not produced convincing evidence that cardiovascular disease is prevented with the use of PPARalpha and PPARgamma agonists.