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: the STOP-NIDDM trial.
Peroxisome proliferator-activated receptor (PPAR)-delta regulates fatty acid oxidation and improves insulin sensitivity. We screened six single nucleotide polymorphisms (SNPs) of the PPAR-delta 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-gamma coactivator-1alpha 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-gamma2 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-delta 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.
Andrulionyte
Laura
L
Department of Medicine, University of Kuopio, 70210 Kuopio, Finland.
Peltola
Paula
P
Chiasson
Jean-Louis
JL
Laakso
Markku
M
D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D018149:Glucose Intolerance / Q000453:epidemiology / Q000235:genetics*; D005998:Glycine; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D047494:PPAR delta / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012694:Serine; D014157:Transcription Factors / Q000235:genetics*
D006360:Heat-Shock Proteins; D047494:PPAR delta; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D012694:Serine; D005998:Glycine