Genetic Epidemiological Study of Venous Thromboembolism and Hemostatic Factors

描述（由申请人提供）：静脉血栓栓塞（VTE）是一种常见病和重要的公共卫生问题。环境和遗传风险因素已被证明是重要的，最近的研究证据表明，基因-环境相互作用是静脉血栓栓塞的病因。先前发现的基因变异只能解释静脉血栓栓塞风险的一小部分。新研究者提出的这项研究的目的是确定参与止血系统重要途径的基因变异，这些基因变异有助于静脉血栓栓塞的风险及其中间表型的变异。VTE表型来源于血栓栓塞病因学纵向调查（LITE），其中包括社区动脉粥样硬化风险（ARIC）和心血管健康研究（CHS）。预计从凝血、血小板聚集和急性期反应信号通路中选择的116个候选基因中的3447个snp是该应用的主要焦点。这些snp是在候选基因关联资源（CARe）研究的队列中测量的，该研究包括ARIC、CHS、动脉粥样硬化多民族研究（MESA）和弗雷明汉心脏研究（FHS）队列。利用CARe和ARIC研究的基因型和表型资源，我们提出了四个目标：1)在LITE的白人参与者中，选择候选基因snp与VTE之间进行纵向遗传关联分析，包括至少14,841名基线时有VTE风险的参与者和16年随访期间确定的489例VTE病例。这将包括个体SNP分析，基因-基因和基因-环境相互作用的测试，以及基于途径的方法。2)在至少10279名白人和3680名非裔美国人ARIC队列中，对所选候选基因snp与VTE相关的重要中间表型进行遗传关联分析。中间表型包括血浆viii因子水平，血管性血友病因子和活化的部分凝血活素时间。3)使用梅奥诊所的静脉血栓栓塞研究（1500例静脉血栓栓塞病例和1500例对照），或使用CARe联盟的其他队列（包括FHS、CHS和MESA）或Caerphilly研究（一项基于英国人群的流行病学研究）中的中间表型，来测试与静脉血栓栓塞显著遗传关联的复制。4)通过对VTE的LITE和中间表型的ARIC中的额外snp进行基因分型来饱和Aim 3中鉴定的基因。我们的研究将为静脉血栓栓塞及其中间表型的遗传决定因素提供重要的新信息，可能为静脉血栓栓塞的预防或治疗提供新的机会。公共卫生相关性：拟议的研究将提供对静脉血栓栓塞的遗传决定因素及其在人群水平上的中间表型的更好理解，并可能为静脉血栓栓塞的预防或治疗提供新的机会。

DESCRIPTION (provided by applicant): Venous thromboembolism (VTE) is a common disease and an important public health problem. Both environmental and genetic risk factors have been documented to be important and evidence from recent studies suggests gene-environment interactions in the etiology of VTE. Previously identified genetic variants only explain a small proportion of VTE risk. The objective of the proposed study, from a new investigator, is to identify variants in genes involved in important pathways of the hemostasis system that contribute to the risk of VTE and the variation of its intermediate phenotypes. The VTE phenotype derives from the Longitudinal Investigation of Thromboembolism Etiology (LITE), which includes the Atherosclerosis Risk in Communities (ARIC) and the Cardiovascular Health Study (CHS). An anticipated 3447 SNPs in 116 candidate genes, selected from coagulation, platelet aggregation, and acute phase response signaling pathways, are the main focus of the application. These SNPs are measured on the cohorts of the Candidate-gene Association REsource (CARe) Study, which includes the ARIC, CHS, Multi-Ethnic Study of Atherosclerosis (MESA), and Framingham Heart Study (FHS) cohorts. Utilizing the genotype and phenotype resources from the CARe and ARIC Studies, we propose four aims: 1) To perform longitudinal genetic association analyses between the selected candidate gene SNPs and VTE in the white participants of LITE, including at least 14,841 participants at risk for VTE at baseline and 489 VTE cases identified during 16 years of follow-up. This will include Individual SNP analysis, tests of gene-gene and gene-environment interactions, and a pathway-based approach. 2) To perform genetic association analyses between the selected candidate gene SNPs and important intermediate phenotypes related to VTE in at least 10,279 whites and 3680 African Americans of the ARIC cohort. The intermediate phenotypes include plasma levels of factor VIIIc, von Willebrand factor, and activated partial thromboplastin time. 3) To test for replication of significant genetic associations with VTE using a Mayo Clinic VTE study (1500 VTE cases and 1500 controls), or with the intermediate phenotypes using other cohorts in the CARe Consortium including the FHS, CHS, and MESA, or the Caerphilly Study, a UK population-based epidemiological study. 4) To saturate genes identified in Aim 3 by genotyping additional SNPs in LITE for VTE and in ARIC for the intermediate phenotypes. Our study will provide important new information on the genetic determinants of VTE and its intermediate phenotypes, potentially providing new opportunities in the prevention or treatment of VTE. PUBLIC HEALTH RELEVANCE: The proposed study will provide greater understanding of the genetic determinants of venous thromboembolism and it intermediate phenotypes at the population level and potentially provide new opportunities for the prevention or treatment of venous thromboembolism.