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Activation of peroxisome proliferator-activated receptor alpha (PPARα) occurs in animal models of diabetes (DM) and is implicated in pathological responses to myocardial ischemia. Using bioinformatics, we identified a single nucleotide polymorphism (SNP) in the PPARα gene promoter ( PPARA  −54,642 G>A; rs135561) that altered the consensus sequence for a nuclear receptor binding site. Electrophoretic mobility shift assays showed that the domain bound two known  PPARA  transcriptional activators, estrogen-related receptor (ERR)-α and -γ and that  PPARA  G bound with greater affinity than  PPARA  A (>2-fold; P<0.05). Likewise, promoter-reporter analyses showed enhanced transcriptional activity for  PPARA  G vs.  PPARA  A for both ERR-α and -γ (3.1 vs.1.9-fold; P<0.05). Since PPARα activation impairs post-ischemic cardiac function in experimental models of DM, we tested whether decreased  PPARA  transcription in  PPARA  A carriers favorably impacted outcome after acute coronary ischemia in 705 patients hospitalized with acute coronary syndromes (ACS; 552 Caucasian, 106 African American).  PPARA  A allele frequencies were similar to non-diseased subjects. However,  PPARA  genotype correlated with 5-year mortality in diabetic (22.2% AA vs. 18.8% AG vs. 39.5% GG; P = 0.008), but not non-diabetic (P = 0.96) subjects (genotype by diabetes interaction P = 0.008). In the diabetic ACS subjects,  PPARA  A carriers had strikingly reduced all-cause mortality compared to  PPARA  G homozygotes, (unadjusted HR 0.44, 95% CI 0.26–0.75; P = 0.003; adjusted HR 0.48, 95% CI 0.27–0.83; P = 0.009). Consistent with previous descriptions of PPARα in experimental models and human disease, we describe a novel  PPARA  promoter SNP that decreases transcriptional activation of  PPARA  and protects against mortality in diabetic patients after ACS.

A PPARα Promoter Variant Impairs ERR-Dependent Transactivation and Decreases Mortality after Acute Coronary Ischemia in Patients with Diabetes