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: 7740762
• 负责人: Weihong Tang
• 金额: $ 28.89万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740762
• 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; public health relevance; 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-环境相互作用的VTE的病因。以前发现的遗传变异只能解释一小部分VTE风险。由一名新研究者进行的拟议研究的目的是确定参与止血系统重要途径的基因变异，这些基因变异导致VTE风险及其中间表型变异。VTE表型来自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）。该应用的主要焦点是116个候选基因中的预计3447个SNP，这些候选基因选自凝血、血小板聚集和急性期反应信号通路。这些SNP是在数据库-基因关联资源（CARe）研究的队列中测量的，该研究包括ARIC、CHS、多种族动脉粥样硬化研究（梅萨）和心脏病研究（FHS）队列。利用来自CARe和ARIC研究的基因型和表型资源，我们提出了四个目标：1）在LITE的白色参与者中进行所选候选基因SNP与VTE之间的纵向遗传关联分析，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，以及基于路径的方法。2)在ARIC队列的至少10，279名白人和3680名非洲裔美国人中，对选定的候选基因SNP和与VTE相关的重要中间表型进行遗传关联分析。中间表型包括凝血因子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)使用马约诊所VTE研究（1500例VTE病例和1500例对照），或使用CARe联盟的其他队列（包括FHS、CHS和梅萨）或Caerphilly研究（一项英国基于人群的流行病学研究），检测与VTE的显著遗传关联的复制。4)通过在LITE中对VTE进行基因分型以及在ARIC中对中间表型进行基因分型，使Aim 3中鉴定的基因饱和。我们的研究将为VTE及其中间表型的遗传决定因素提供重要的新信息，可能为预防或治疗VTE提供新的机会。公共卫生相关性：拟议的研究将提供更好的了解静脉血栓栓塞症的遗传决定因素，它在人群水平的中间表型，并可能提供新的机会，预防或治疗静脉血栓栓塞症。