Coronary artery bypass graft (CABG) surgery is performed on 500,000 individuals annually in the U.S. Coronary bypass graft failure remains a significant problem, eluding pharmacological therapy. An estimated 15-20 percent vein grafts fail at 1 year, 30-40 percent at 5 years, and >40 percent fail at 10 years. Neointimal hyperplasia and subsequent accelerated atherosclerosis are felt responsible factors in a process ultimately resulting in graft occlusion and adverse myocardial events, but specific molecular/cellular mechanisms involved remain poorly understood. Risk stratification based on clinical, angiographic, procedural and biological markers is only partially successful, with significant unexplained variability in long-term outcomes after CABG surgery. This proposal (GENE-MAGIC) examines genetic mechanisms underlying development and consequences Of vein graft failure after CABG.
Two specific aims i nclude: 1) test association between candidate gene polymorphisms and angiographic vein graft phenotypes, 2) examine role of candidate gene polymorphisms in progression to major adverse cardiac events following CABG. The current proposal is a sub-study of the ongoing PREVENT IV trial, a large multi-center clinical trial designed to examine the efficacy of a novel anti-proliferative agent in the incidence of vein graft occlusion after CABG. Using an inception cohort study design, GENE-MAGIC will enroll 2000 patients presenting for 1 year angiographic follow-up after CABG. We have selected 92 candidate genes potentially important in pathogenesis of vein graft stenosis either as implicated in functional genomic pathways, structural genomic clusters related to vascular remodeling, identified through transcriptional profiling or proteomic analysis, and/or co-localized by linkage in genome scans or population-based association studies. Of these, special emphasis will be placed on 25 genes involved in modulating the activated vascular smooth muscle cell phenotype in vein grafts. With the use of public databases, we further selected 198 polymorphisms in these genes, with previously demonstrated or high likelihood of functionally significant effects on the gene product, as well as 58 variants important in determining population admixture. The statistical approach will proceed from univariate and multivariate analyses for association of each polymorphism utilizing pre-defined angiographic/clinical endpoints, followed by more complex statistical and data mining techniques to assess multi-locus and gene-environment interactions, as well as haplotype associations, while controlling for population structure. By investigating the impact of multi-locus genetic variations on vein graft disease using both a narrowly-defined quantitative phenotype and a long-term clinical end point in a large patient population, GENE-MAGIC is intended to fill some of the gaps left by previous underpowered single-gene association studies. Such genetic information may help in stratifying mortality and morbidity in CABG patients, improve prognostication, and direct medical decisionmaking preoperatively (surgery versus medical risk), intraoperatively (choice of bypass conduit), and in postoperative follow-up (frequency of coronary graft surveillance), and may have ramifications for other revascularization procedures.
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