Genetics Myocardial Adverse Outcomes/Graft Failure-CABG

描述（由申请人提供）：在美国，每年有50万人进行冠状动脉旁路移植术（CABG）手术，冠状动脉旁路移植术失败仍然是一个重要的问题，逃避药物治疗。据估计，15- 20%的静脉移植在1年内失败，30- 40%在5年内失败，10年内40%失败。内膜增生和随后的动脉粥样硬化加速被认为是最终导致移植物闭塞和不良心肌事件的过程中的负责因素，但具体的分子/细胞机制尚不清楚。基于临床、血管造影、程序和生物学标记的风险分层仅部分成功，CABG手术后的长期结果存在无法解释的显著差异。这项提议（GENE-MAGIC）研究了CABG术后静脉移植衰竭的遗传机制。两个具体目的包括：1)测试候选基因多态性与血管造影静脉移植表型之间的关联；2)检查候选基因多态性在冠脉搭桥后主要不良心脏事件进展中的作用。目前的提案是正在进行的prevention IV试验的一个子研究，这是一项大型多中心临床试验，旨在检查一种新型抗增殖药物对CABG后静脉移植闭塞发生率的疗效。采用初始队列研究设计，GENE-MAGIC将招募2000名冠脉搭桥后进行1年血管造影随访的患者。我们选择了92个在静脉移植物狭窄发病机制中可能重要的候选基因，这些基因可能与功能基因组途径有关，与血管重塑相关的结构基因组簇，通过转录谱分析或蛋白质组学分析确定，以及/或通过基因组扫描或基于人群的关联研究中的连锁共定位。其中，特别强调将放在25个基因参与调节激活血管平滑肌细胞表型在静脉移植物。通过使用公共数据库，我们进一步选择了这些基因中的198个多态性，这些多态性先前已经证明或很可能对基因产物产生功能上的显著影响，以及58个对确定群体混合很重要的变异。统计方法将从单变量和多变量分析开始，利用预先定义的血管造影/临床终点分析每种多态性的关联，然后使用更复杂的统计和数据挖掘技术来评估多位点和基因与环境的相互作用，以及单倍型关联，同时控制种群结构。通过在大量患者群体中使用狭义定量表型和长期临床终点来研究多位点遗传变异对静脉移植物疾病的影响，GENE-MAGIC旨在填补以前单基因关联研究不足留下的一些空白。这些遗传信息可能有助于对冠状动脉搭桥患者的死亡率和发病率进行分层，改善预后，指导术前（手术与医疗风险）、术中（旁路导管的选择）和术后随访（冠状动脉移植物监测频率）的医疗决策，并可能对其他血运重建手术产生影响。

DESCRIPTION (provided by applicant): 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 include: 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.