Genetics Myocardial Adverse Outcomes/Graft Failure-CABG

描述（由申请人提供）：在美国，每年有500，000人接受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大问题，无法进行药物治疗。 据估计，15- 20%的静脉移植物在1年时失败，5年时失败30- 40%，10年时失败> 40%。 新生内膜增生和随后的加速动脉粥样硬化是最终导致移植物闭塞和不良心肌事件的过程中的负责任因素，但涉及的具体分子/细胞机制仍知之甚少。 基于临床、血管造影、手术和生物学标志物的风险分层仅部分成功，CABG手术后长期结局存在显著的无法解释的变异性。 本提案（GENE-MAGIC）研究了CABG后静脉移植失败的潜在发展和后果的遗传机制。 两个具体目标包括：1）测试候选基因多态性与血管造影静脉移植物表型之间的关联，2）检查候选基因多态性在CABG后主要不良心脏事件进展中的作用。 目前的提议是正在进行的PREVENT IV试验的子研究，PREVENT IV试验是一项大型多中心临床试验，旨在检查新型抗增殖药物在CABG后静脉移植物闭塞发生率中的疗效。 采用初始队列研究设计，GENE-MAGIC将入组2000例患者，接受CABG术后1年血管造影随访。 我们已经选择了92个候选基因，这些基因在静脉移植物狭窄的发病机制中可能是重要的，它们涉及功能基因组途径、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鉴定、和/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，将特别强调25个基因参与调节静脉移植物中活化的血管平滑肌细胞表型。 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个在确定群体混合中重要的变体。 统计方法将从使用预定义的血管造影/临床终点的每种多态性关联的单变量和多变量分析开始，然后是更复杂的统计和数据挖掘技术，以评估多位点和基因-环境相互作用，以及单倍型关联，同时控制群体结构。 通过在大量患者人群中使用狭义的定量表型和长期临床终点研究多位点遗传变异对静脉移植物疾病的影响，GENE-MAGIC旨在填补以前动力不足的单基因关联研究留下的一些空白。 这些遗传信息可能有助于对CABG患者的死亡率和发病率进行分层，改善诊断，并指导术前（手术与医疗风险）、术中（旁路管道的选择）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.