Thrombogenic Factors and Recurrent Coronary Events

这项持续资助的主要目的是确定在心肌梗死后患者的长期随访中，18个预先指定的基因位点（多态性）是否对时间依赖性复发性冠状动脉事件（不稳定型心绞痛、非致死性心肌再梗死或冠状动脉死亡）的发生有显著的附加风险。次要目的是确定预先指定的循环脂质因子和脂质相关基因型是否与止血激活增加有关。研究人群包括1045例梗死后患者，其中202例在平均2年随访期间首次复发心脏事件。基因检测和额外的凝血和脂质检测将在本队列入组前收集并在零下70摄氏度冷冻的白细胞样本、血浆和血清中进行。基因型鉴定将包括6个与凝血蛋白相关的基因座，3个与参与血栓形成的粘附分子相关的基因座，9个与载脂蛋白和富甘油三酯脂蛋白代谢相关的基因座。一种创新的基因载体方法将用于初步分析，以确定18个预先指定的基因型是否对这一定义明确的不相关专利队列中的时间依赖性复发性心脏事件具有附加易感性。确定的遗传风险将表示为每个个体存在的每个风险位点数量的平均风险比，并适当调整生物、疾病严重程度和环境协变量。在这个心肌梗死后队列中，该研究有90%的能力检测到每个人每个数量或预先指定的风险位点（范围0到8 +）显著增加15%或更高的平均风险（风险比大于1.15）。识别由有限的风险基因型构成的冠状动脉复发事件的附加风险，将在未来识别和量化个体风险基因型在这种少源性疾病中所起作用的筛选技术中发挥作用。

The primary objective of this continuation grant is to determine if 18 prespecified genetic loci (polymorphisms)that code for proteins involved in coagulation-lipid-risk mechanisms contribute significant additive risk for the occurrence of time-dependent recurrent coronary events (unstable angina, non-fatal myocardial reinfarction, or coronary death) during long-term follow-up in an enriched population of post-myocardial infarction patients. The secondary objective is to determine if prespecified circulating lipid factors and lipid related genotypes are associated with increased hemostatic activation. The study population involves 1,045 post-infarction patents with 202 first recurrent cardiac events that occurred during an average 2-year follow-up. Genetic testing and additional coagulation and lipid tests will be performed on white blood cell samples, plasma, and serum that were collected and frozen at minus 70 Celsius during the prior enrollment of this cohort. Genotype identification will include 6 loci related to coagulation proteins, 3 related to adhesion molecules involved in thrombosis, and 9 involved in apolipoproteins and metabolism of triglyceride-rich lipoproteins. An innovative genetic carriership approach will be used in the primary analysis to determine if a pool of the 18 prespecified genotypes contributes additive susceptibility for time-dependent recurrent cardiac events in this well-defined cohort of unrelated patents. The identified genetic risk will be expressed as an average hazard ratio per number of risk loci present per individual, with appropriate adjustment for biologic, disease severity, and environmental covariates. The study has 90 percent power to detect a significantly increased average risk of 15percent or greater (hazard ratio greater than 1.15) per number or prespecified risk loci present (range 0 to 8 plus) per individual in this post-myocardial infarction cohort. Identification of an additive risk posed by a limited pool of risk genotypes in recurrent coronary events will be useful as a screening technique in the future identification and quantification of the role played by individual risk genotypes in this oligogenic disorder.