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

• Published in: PloS one Vol. 5; no. 9; p. e12584
• Main Authors: Cresci, Sharon, Huss, Janice M., Beitelshees, Amber L., Jones, Philip G., Minton, Matt R., Dorn, Gerald W., Kelly, Daniel P., Spertus, John A., McLeod, Howard L.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.09.2010; Public Library of Science (PLoS)
• Subjects: Aged; Animal models; Apolipoproteins; Atherosclerosis; Base Sequence; Binding sites; Bioinformatics; Blood & organ donations; Cardiovascular Disorders/Coronary Artery Disease; Cardiovascular Disorders/Myocardial Infarction; Carriers; Cohort Studies; Consent; Conserved sequence; Coronary Disease - genetics; Coronary Disease - metabolism; Coronary Disease - mortality; Deoxyribonucleic acid; Diabetes; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes mellitus; Diabetic Cardiomyopathies - genetics; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - mortality; DNA; Electrophoretic mobility; ERRalpha Estrogen-Related Receptor; Estrogens; Fatty acids; Female; Gene expression; Gene frequency; Gene polymorphism; Genetic engineering; Genetic testing; Genetic Variation; Genetics and Genomics/Functional Genomics; Genotype; Haplotypes; Heart attacks; Heart diseases; Homozygotes; Humans; Hypertension; Insulin; Ischemia; Lipids; Male; Medical research; Medicine; Metabolism; Middle Aged; Molecular Biology/Translation Mechanisms; Molecular Sequence Data; Mortality; Myocardial ischemia; Myocardial Ischemia - genetics; Myocardial Ischemia - metabolism; Myocardial Ischemia - mortality; Patients; Plasma; Polymorphism; Polymorphism, Single Nucleotide; PPAR alpha - genetics; Promoter Regions, Genetic; Prospective Studies; Protein Binding; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Rodents; Single-nucleotide polymorphism; Transcription activation; Transcription factors; Transcriptional Activation; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012584

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.