Peroxisome Proliferator-Activated Receptor α Gene Variation Influences Age of Onset and Progression of Type 2 Diabetes

Abstract

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)α is a master regulator of fatty acid catabolism, and PPARα activators delay the onset of type 2 diabetes. We examined association between three PPARα gene polymorphisms (an A→C variant in intron 1, the L162V variant, and the intron 7 G→C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARα gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A→C (P < 0.001) and intron 7 G→C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARα haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis ≤45 years) of 3.75 (95% CI 1.65–8.56, P = 0.002). Intron 1 C-allele carriers also progressed more rapidly to insulin monotherapy (AA 9.4 ± 1.5 and AC + CC 5.3 ± 1.1 years, P = 0.002). These data indicate that PPARα gene variation influences the onset and progression of type 2 diabetes.