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Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes.
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Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)a is a master regulator of fatty acid catabolism, and PPA-Ralpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha 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, PPARalpha 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 PPARalpha 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 less than or equal to45 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 PPARalpha gene variation influences the onset and progression of type 2 diabetes.
|Title:||Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes|
|Keywords:||NONESTERIFIED FATTY-ACIDS, CORONARY-ARTERY-DISEASE, PPAR-GAMMA ACTIVATION, (PPAR)-ALPHA ACTIVATION, POLYMORPHISM, ASSOCIATION, MUTATION, RISK, RATS|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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