Peroxisome proliferator-activated receptor pathway gene polymorphism associated with extent of coronary artery disease in patients with type 2 diabetes in the bypass angioplasty revascularization investigation 2 diabetes trial

Abstract

Background: Coronary artery disease (CAD) is the major cause of death in patients with type 2 diabetes mellitus. Although demographic and clinical factors associated with extent of CAD in patients with diabetes mellitus have been described, genetic factors have not. We hypothesized that genetic variation in peroxisome proliferator-activated receptor (PPAR) pathway genes, important in diabetes mellitus and atherosclerosis, would be associated with extent of CAD in patients with diabetes mellitus.

Methods and results: We genotyped 1043 patients (702 white, 175 blacks) from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) genetic cohort for 3351 variants in 223 PPAR pathway genes using a custom targeted-genotyping array. Angiographic end points were determined by a core laboratory. In whites, a single variant (rs1503298) in TLL1 was significantly (P=5.5 × 10(-6)) associated with extent of CAD, defined as number of lesions with percent diameter stenosis ≥20%, after stringent Bonferroni correction for all 3351 single nucleotide polymorphisms. This association was validated in the diabetic subgroups of 2 independent cohorts, the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) post-myocardial infarction registry and the prospective Family Heart Study (FHS) of individuals at risk for CAD. TLL1rs1503298 was also significantly associated with extent of severe CAD (≥70% diameter stenosis; P=3.7 × 10(-2)) and myocardial jeopardy index (P=8.7 × 10(-4)). In general linear regression modeling, TLL1rs1503298 explained more variance of extent of CAD than the previously determined clinical factors.

Conclusions: We identified a variant in a single PPAR pathway gene, TLL1, that is associated with the extent of CAD independently of clinical predictors, specifically in patients with type 2 diabetes mellitus and CAD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Figures

Figure 1

Comparison of clinical covariates associated with number of lesions ≥ 20% in the BARI 2D genetic cohort (right) compared with the entire BARI 2D cohort (left).

Figure 2

Results of tests for a trend in the association between number of lesions ≥ 20% and each SNP on custom chip in Caucasians in BARI 2D. Red line depicts threshold for statistical significance after Bonferroni correction for multiple comparisons.

Figure 3

(A) Mean (±SE) residual of number of lesions ≥ 20% by TLL1 rs1503298 genotype after adjustment for age, sex and BMI in Caucasian BARI 2D subjects. (B) Number of lesions ≥ 20% by genotype for the average BARI 2D subject (a 63 year old male with BMI of 30).

Figure 4

Mean (±SE) residual of number of lesions ≥ 70% (A) and myocardial jeopardy index (B) by TLL1 rs1503298 genotype after adjustment for age, sex and BMI in Caucasian BARI 2D subjects.