Abstract 2186: PPAR-Pathway Gene Polymorphisms Associated With Extent of Coronary Artery Disease in Patients With Type 2 Diabetes in the BARI 2D Trial
Background: Coronary artery disease (CAD) is the major cause of morbidity and mortality in patients (pts) with type 2 diabetes (DM). While demographic and clinical factors have been associated with extent of CAD in pts with DM, genetic factors associated with extent of CAD in pts with DM are not well defined. We tested whether genetic variation in peroxisome proliferator-activated receptor (PPAR)-pathway genes, known to be important in DM and atherosclerosis, were independently associated with the extent of CAD in pts with DM enrolled in the BARI 2D randomized clinical trial.
Methods: 1,043 pts (702 Caucasian; 175 African Americans) with CAD and DM from BARI 2D who consented for genetic analysis were genotyped for 3,351 single nucleotide polymorphisms (SNPs) in 223 PPAR-pathway genes utilizing a custom targeted-genotyping array. Number of lesions, % diameter stenosis (DS), and myocardial jeopardy index (MJI) were determined from baseline coronary angiograms by a core lab. Number of lesions ≥ 20% DS was the primary endpoint for this analysis. In Caucasians (largest racial subgroup), stepwise regression was used for each gene to select clinical covariates and SNPs within the gene that significantly predicted CAD extent. Association analyses were performed using the model including clinical covariates and the model including clinical covariates as well as the significant SNPs within that gene. Gene effect was determined by the likelihood ratio test of the second model against the first as χ2 = (−2 ln Lcovariates & SNPs)−(−2 ln Lcovariates); significance level was 2.24 × 10−4 using Bonferroni correction for all 223 genes. We tested significant associations in a separate cohort of pts with CAD and DM from the multicenter TRIUMPH study.
Results: We identified 5 genes (ESRRG (16 significant SNPs; p = 1.2 × 10−4) MYH14 (3 SNPs; p = 2.5 × 10−5), RORA (24 SNPs; p = 5.0 × 10−8), THRB (12 SNPs; p = 2.1 × 10−4), TLL1 (4 SNPs; p = 3.8 × 10−6)) that were associated with extent of CAD in pts with DM. These genes also showed significant association with MJI. All 5 associations remained significant (p<0.01) in the replication cohort.
Conclusions: We have identified 5 PPAR-pathway genes that are associated with the extent of CAD, independent of clinical predictors, in pts with type 2 DM and CAD.