A PPARα promoter variant impairs ERR-dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes.
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.
Cresci
Sharon
S
Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
Huss
Janice M
JM
Beitelshees
Amber L
AL
Jones
Philip G
PG
Minton
Matt R
MR
Dorn
Gerald W
GW
Kelly
Daniel P
DP
Spertus
John A
JA
McLeod
Howard L
HL
D000368:Aged; D001483:Base Sequence; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D047493:PPAR alpha / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097983:ERRalpha Estrogen-Related Receptor
D047493:PPAR alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C490917:ESRRG protein, human