Abstract 3190: Mortality in Diabetic Acute Coronary Syndrome Patients is Associated with a Novel Variant in the PPAR alpha Gene Promoter that Confers Differential ERR Binding
Background: Diabetes mellitus (DM) is associated with increased adverse cardiovascular events in patients with acute coronary syndromes (ACS). Activation of peroxisome proliferator-activated receptor alpha (PPARα) may contribute to metabolic derangements in DM and exacerbate pathological responses to myocardial ischemia. We hypothesized that polymorphisms of the PPAR> gene (PPARA) would be associated with variability in outcome following ACS in patients with DM.
Methods and Results: 735 patients hospitalized with ACS were genotyped at a polymorphic site that altered a putative nuclear receptor consensus half-site within the promoter of PPARA (PPARA −54,642 G>A). 3-year mortality was analyzed in relation to PPARA genotype and DM status. A novel polymorphism (PPARA −54,645 C>T) was identified adjacent to, and in complete LD with, PPARA −54,642 G>A. PPARA genotype was associated with mortality in a gene dose-dependent manner (15% TT/AA vs. 37% TC/AG vs. 48% CC/GG; p=0.005) in diabetic, but not in non-diabetic ACS patients. In addition, there was a significant genotype by diabetes interaction (p=0.008). After multivariable adjustment, PPARA genotype remained an independent predictor of 3-year mortality. Diabetic ACS patients homozygous for the PPARA −54,645/−54,642 CC/GG genotype had a greater than 5-fold relative increase in 3-year mortality (HR 5.25, 95% CI 1.09–39.79) compared with PPARA -54,645/−54,642 TT/AA homozygotes (heterozygote HR =1.35, 95% CI 0.28–9.89, compared with PPARA −54,645/−54,642 TT/AA homozygotes). Electromobility shift assays performed to investigate binding of estrogen-related receptor (ERR) orphan nuclear receptors, known activators of PPARαgene expression, demonstrated increased binding of ERR agr; and γ to a nucleotide probe containing the variant CG sequence compared with a probe containing the variant TA sequence.
Conclusions: We have identified a novel polymorphism within the PPARA promoter that is strongly associated with 3-year mortality in diabetic ACS patients. This association may result from differential binding of ERR agr; and γ to the PPARA promoter causing altered expression of PPAR agr; during myocardial ischemia. These findings suggest a novel potential therapeutic target for diabetic ACS patients.