Genetic Epidemiological Study of Venous Thromboembolism and Hemostatic Factors

描述(申请人提供)：静脉血栓栓塞症(VTE)是一种常见疾病，也是一个重要的公共卫生问题。环境和遗传风险因素都被证明是重要的，最近研究的证据表明，基因-环境相互作用在VTE的病因中。以前发现的基因变异只能解释一小部分静脉血栓栓塞症的风险。这项由一位新的研究人员提出的研究的目的是确定止血系统重要通路中涉及的基因变异，这些变异导致VTE的风险及其中间表型的变化。VTE表型来源于血栓栓塞症病因纵向调查(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)。从凝血、血小板聚集和急性时相反应信号通路中选择的116个候选基因中预计有3447个SNPs是应用的主要焦点。这些SNP是根据候选基因关联资源(CARE)研究的队列进行测量的，该研究包括ARIC、CHS、动脉粥样硬化多种族研究(MESA)和Framingham心脏研究(FHS)队列。利用CARE和ARIC研究中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，包括至少14841名VTE高危参与者和16年随访中发现的489例VTE病例，进行选定候选基因SNPs与VTE之间的纵向遗传关联分析。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ARIC队列中至少10,279名白人和3680名非裔美国人中，进行所选候选基因SNPs与VTE相关重要中间表型之间的遗传关联分析。中间表型包括血浆VIIIc因子、von Willebrand因子和活化部分凝血活酶时间。3)使用Mayo Clinic VTE研究(1500例VTE病例和1500例对照)，或使用CARE联盟中的其他队列(包括FHS、CHS和MESA)或英国人群流行病学研究CaerPhilly研究，测试与VTE显著的遗传关联的重复性。4)通过在用于VTE的LITE和用于中间表型的ARIC中对额外的SNPs进行基因分型，使在Aim 3中确定的基因饱和。我们的研究将为VTE的遗传决定因素及其中间表型提供重要的新信息，可能为VTE的预防或治疗提供新的机会。公共卫生相关性：拟议的研究将更好地了解静脉血栓栓塞症的遗传决定因素及其在人群水平上的中间表型，并可能为静脉血栓栓塞症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.