Genetic Epidemiological Study of Venous Thromboembolism and Hemostatic Factors

静脉血栓栓塞与止血因素的遗传流行病学研究

• 批准号: 8277231
• 负责人: Weihong Tang
• 金额: $ 28.6万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277231
• 关键词: Activated Partial Thromboplastin Time measurement; Acute-Phase Reaction; African American; Age; Atherosclerosis; Blood typing procedure; Candidate Disease Gene; Cardiovascular system; Clinic; Coagulation Process; Communities; Data Set; Diabetes Mellitus; Disease; Environmental Risk Factor; Epidemiologic Studies; Etiology; Fibrinogen; Framingham Heart Study; Genes; Genetic; Genetic Determinism; Genotype; Haplotypes; Health; Hemostatic Agents; Hemostatic function; Individual; Investigation; Linkage Disequilibrium; Measures; Obesity; Outcome; Parents; Participant; Pathway interactions; Phenotype; Plasma; Platelet aggregation; Population; Population Study; Prevention; Public Health; Research Personnel; Resources; Risk; SNP genotyping; Sampling; Signal Pathway; Structure; System; Testing; Thromboembolism; Variant; Venous; base; blood group; cohort; factor V Leiden; follow-up; gene environment interaction; gene interaction; genetic association; genetic risk factor; genetic variant; genome wide association study; improved; population based; sex; von Willebrand Factor

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.

描述（申请人提供）：静脉血栓栓塞（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均已被证明很重要，最近研究的证据表明基因与环境的相互作用在 VTE 的病因学中。之前发现的基因变异只能解释一小部分 VTE 风险。一位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，这些变异会导致 VTE 风险及其中间表型的变异。 VTE 表型源自血栓栓塞病因纵向调查 (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)。预计 116 个候选基因中的 3447 个 SNP，选自凝血、血小板聚集和急性期反应信号通路，是该申请的主要焦点。这些 SNP 在候选基因关联资源 (CARe) 研究队列中进行测量，其中包括 ARIC、CHS、动脉粥样硬化多种族研究 (MESA) 和弗雷明汉心脏研究 (FHS) 队列。利用来自 CARe 和 ARIC 研究的基因型和表型资源，我们提出四个目标：1）在 LITE 的白人参与者中，对所选候选基因 SNP 和 VTE 之间进行纵向遗传关联分析，其中包括至少 14,841 名基线时有 VTE 风险的参与者和 16 年随访期间发现的 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) 对 ARIC 队列中至少 10,279 名白人和 3680 名非裔美国人中选定的候选基因 SNP 和与 VTE 相关的重要中间表型之间进行遗传关联分析。中间表型包括因子 VIIIc、血管性血友病因子和活化部分凝血活酶时间的血浆水平。 3) 使用 Mayo Clinic VTE 研究（1500 个 VTE 病例和 1500 个对照）来测试与 VTE 的显着遗传关联的复制，或者使用 CARe 联盟中的其他队列（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）来测试与中间表型的显着遗传关联的复制。 4) 通过在 LITE 中对 VTE 和 ARIC 中对中间表型进行额外 SNP 基因分型，使目标 3 中鉴定的基因饱和。我们的研究将提供有关 VTE 及其中间表型的遗传决定因素的重要新信息，可能为预防或治疗 VTE 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的遗传决定因素及其在人群水平上的中间表型，并可能为预防或治疗静脉血栓栓塞提供新的机会。