Genetics Myocardial Adverse Outcomes/Graft Failure-CABG

描述(申请人提供)：美国每年有500,000人接受冠状动脉旁路移植(CABG)手术。冠状动脉旁路移植失败仍然是一个严重的问题，无法进行药物治疗。据估计，15%-20%的静脉移植在1年失败，30%-40%的静脉移植在5年失败，40%的静脉移植在10年失败。新生内膜增生和随后加速的动脉粥样硬化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责任因素，但涉及的具体分子/细胞机制仍不清楚。基于临床、血管造影、程序和生物标记物的风险分层仅有部分成功，CABG手术后长期结果具有显著的不可解释的变异性。这项建议(基因魔术)研究了CABG后静脉移植失败的潜在遗传机制和后果。两个具体目标包括：1)检测候选基因多态与血管造影静脉移植物表型之间的关系，2)检测候选基因多态在冠状动脉旁路移植术后进展为主要不良心脏事件中的作用。目前的建议是正在进行的预防IV试验的子研究，该试验是一项大型多中心临床试验，旨在检查一种新型抗增殖剂对冠状动脉搭桥术后静脉移植物闭塞的疗效。采用初始队列研究设计，GENE-MAGIC将招募2000名患者，在冠状动脉搭桥术后进行为期一年的血管造影随访。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、与血管重塑相关的结构基因组簇有关，通过转录图谱或蛋白质组分析鉴定，和/或通过基因组扫描或基于群体的关联研究中的连锁而共同定位。其中，将特别强调25个基因参与调节静脉移植物中激活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，这些多态对基因产物具有或很高的功能显著影响，以及58个在决定种群混合中重要的变种。统计方法将从利用预定义的血管造影/临床终点对每种多态的关联进行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，以评估多基因座和基因-环境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的数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，基因魔术旨在填补先前动力不足的单基因关联研究留下的一些空白。这样的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，改善预后，并在术前(手术与医疗风险)、术中(搭桥管道的选择)和术后随访(冠状动脉移植物监测频率)指导医疗决策，并可能对其他血运重建程序产生影响。

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.