Abstract
BackgroundCommon variants of the PPARA gene have been found to associate with ischaemic heart disease in non diabetic men. The L162V variant was found to be protective while the C2528G variant increased risk. L162V has also been associated with altered lipid measures. We therefore sought to determine the effect of PPARA gene variation on susceptibility to myocardial infarction in patients with type 2 diabetes. 1810 subjects with type 2 diabetes from the prospective Go-DARTS study were genotyped for the L162V and C2528G variants in the PPARA gene and the association of the variants with incident non-fatal myocardial infarction was examined. Cox's proportional hazards was used to interrogate time to event from recruitment, and linear regression for analysing association of genotype with quantitative clinical traits.ResultsThe V162 allele was associated with decreased risk of non-fatal myocardial infarction (HR = 0.31, 95%CI 0.10–0.93 p = 0.037) whereas the C2528 allele was associated with increased risk (HR = 2.77 95%CI 1.34–5.75 p = 0.006). Similarly V162 was associated with a later mean age of diagnosis with type 2 diabetes and C2582 an earlier age of diagnosis. C2528 was also associated with increased total cholesterol and LDL cholesterol, which did not account for the observed increased risk. Haplotype analysis demonstrated that when both rare variants occurred on the same haplotype the effect of each was abrogated.ConclusionGenetic variation at the PPARA locus is important in determining cardiovascular risk in both male and female patients with diabetes. This genotype associated risk appears to be independent of the effect of these genotypes on lipid profiles and age of diagnosis with diabetes.
Highlights
Common variants of the PPARA gene have been found to associate with ischaemic heart disease in non diabetic men
Dysregulation of fatty acid metabolism plays a pivotal role in the aetiology of type 2 diabetes [1], and explains, at least in part, the association between obesity, type 2 diabetes and cardiovascular disease (CVD)
We investigated the association between PPARA gene variation with risk of CVD and diabetes related traits in Caucasian subjects with type 2 diabetes participating in the prospective population-based Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) study [14,15,16]
Summary
Common variants of the PPARA gene have been found to associate with ischaemic heart disease in non diabetic men. 1810 subjects with type 2 diabetes from the prospective Go-DARTS study were genotyped for the L162V and C2528G variants in the PPARA gene and the association of the variants with incident non-fatal myocardial infarction was examined. Ligands for PPARα include polyunsaturated fatty acids and the fibrate class of lipidlowering drugs [2] It is expressed at high levels in several cell types involved in the atherosclerotic process [3], and its activation has beneficial effects on plasma lipids, endothelial function and markers of inflammation [4]. We investigated the association between PPARA gene variation with risk of CVD and diabetes related traits in Caucasian subjects with type 2 diabetes participating in the prospective population-based Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) study [14,15,16]
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