Genetic and Environmental Risk Factors for Venous Thromboembolism

静脉血栓栓塞的遗传和环境危险因素

• 批准号: 8419717
• 负责人: CHRISTOPHER KABRHEL
• 金额: $ 86.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8419717
• 关键词: American; Attention; Biometry; Blood Clot; Blood coagulation; Body mass index; Build-it; Candidate Disease Gene; Cardiovascular system; Case-Control Studies; Cessation of life; Clinic; Code; Cohort Studies; Collaborations; Custom; Data; Data Collection; Deep Vein Thrombosis; Disease; Employee Strikes; Enrollment; Ensure; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epidemiology; Estrogens; Etiology; Female; Follow-Up Studies; Frequencies; Functional disorder; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genotype; Health Professional; Hormones; Incidence; Individual; Institutes; Malignant Neoplasms; Molecular Genetics; Nurses; Nurses' Health Study; Obesity; Paper; Peer Review; Population; Postmenopause; Prevalence; Prevention; Public Health; Publishing; Pulmonary Embolism; Research; Research Personnel; Risk; Risk Factors; Sampling; Single Nucleotide Polymorphism; Smoking; Staging; Surgeon; Testing; Thromboembolism; To specify; United States; Universities; Validation; Variant; Venous; Work; base; cardiovascular disorder epidemiology; clinical practice; cohort; cost effective; design; exome; experience; flexibility; follow-up; gene environment interaction; genetic risk assessment; genetic risk factor; genetic variant; genome wide association study; genome-wide; improved; innovation; insight; male health; mortality; multidisciplinary; novel; prevent; prospective; public health relevance

DESCRIPTION (provided by applicant): Background: Venous thromboembolism (VTE) strikes 1-2/1000 Americans annually, and is a common cause of cardiovascular death. The etiology of VTE is multi-factorial, with both genetic and environmental factors contributing to incidence. However, known genetic and environmental risk factors explain less than 50% of VTE incidence and genome-wide association studies (GWAS) have been unsuccessful in identifying novel loci. Little is known about possible gene-environment interactions. Setting: This study will be performed by an experienced, multidisciplinary, multi-institutional group of thromboembolism researchers, genetic and cardiovascular epidemiologists, and experts in statistical genetics working at Harvard University and the Mayo Clinic. Investigators on this project have decades of experience conducting genetic and epidemiological studies, and have published hundreds of peer reviewed papers relevant to the current proposal. Research Plan: We will examine data from the Nurses' Health Studies I & II (NHS I&II) and the Health Professionals Follow Up (HPFS) study. NHS I&II and HPFS are ongoing prospective cohort studies of 121,700 and 116,686 female nurses, and 51,529 male health professionals. For each of the three cohorts, data describing VTE and prospective environmental exposures have been collected for more than 25 years. We will perform the first exome wide association study (XWAS) of VTE in 2,500 VTE cases and 2,500 controls, using the newly available Illumina(R) HumanExome BeadChip that includes 220,000 coding genetic variants to a population prevalence of 0.005%. We will replicate our top XWAS findings in an independent clinic-based sample of 2000 VTE cases and 2000 controls from the Mayo Clinic. Additionally, we will include custom content on the exome chip to perform deep replication of the top 5,000 single nucleotide polymorphisms (SNPs) identified in two previously completed VTE GWAS. Lastly, we will study interactions between confirmed genetic polymorphisms and four key environmental risk factors for VTE identified in our prior work: obesity, physical inactivity, smoking, and postmenopausal hormone use. Relevance to Public Health: VTE is a common and deadly disease, a fact highlighted by the Acting Surgeon General of the United States who in 2008 issued a 'Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism' urging "more research on the causes, prevention, and treatment of deep vein thrombosis." The current proposal will be the most comprehensive assessment of genetic and environmental risk factors for VTE to date, will provide insight into the basic pathophysiology of VTE and has the potential to impact clinical practice. Our approach is both innovative and is cost-effective as it builds on decades of prospective data collection from three large cohorts and existing data. Our analyses will result in identification of novel common genetic loci for VTE. Given the high population prevalence of risk factors and the high mortality of VTE, the potential public health impact of this work is large.

描述（申请人提供）：背景：静脉血栓栓塞（VTE）每年袭击1-2/1000的美国人，是心血管死亡的常见原因。VTE的病因是多因素的，遗传和环境因素都有助于发病率。然而，已知的遗传和环境风险因素解释不到50%的VTE发病率，全基因组关联研究（GWAS）在识别新基因座方面一直不成功。对基因与环境之间可能的相互作用知之甚少。周边环境：这栋 本研究将由一个经验丰富的、多学科的、多机构的血栓栓塞研究人员、遗传学和心血管流行病学家以及在哈佛大学和马约诊所工作的统计遗传学专家小组进行。该项目的研究人员拥有数十年的遗传学和流行病学研究经验，并发表了数百篇与当前提案相关的同行评审论文。研究计划：我们将检查护士健康研究I和II（NHS I和II）和卫生专业人员随访（HPFS）研究的数据。NHS I&II和HPFS是正在进行的前瞻性队列研究，包括121，700和116，686名女性护士以及51，529名男性卫生专业人员。对于三个队列中的每一个，描述VTE和预期环境暴露的数据已经收集了超过25年。我们将在2，500例VTE病例和2，500例对照中进行VTE的第一个外显子组广泛关联研究（XWAS），使用新的Illumina（R）HumanExome BeadChip，其中包括220，000个编码遗传变异，人群患病率为0.005%。我们将在来自马约诊所的2000例VTE病例和2000例对照的独立临床样本中复制我们的顶级XWAS发现。此外，我们将在外显子组芯片上包含自定义内容，以深度复制在两个先前完成的VTE GWAS中鉴定的前5，000个单核苷酸多态性（SNP）。最后，我们将研究已证实的遗传多态性与我们先前工作中确定的四个关键环境风险因素之间的相互作用：肥胖，缺乏运动，吸烟和绝经后激素使用。与公共卫生的相关性：静脉血栓栓塞是一种常见的致命疾病，美国代理外科医生在2008年发布了“预防深静脉血栓形成和肺栓塞的行动呼吁”，敦促“对深静脉血栓形成的原因，预防和治疗进行更多的研究。“目前的提案将是迄今为止对VTE遗传和环境风险因素的最全面评估，将提供对VTE基本病理生理学的深入了解，并有可能影响临床实践。我们的方法既具有创新性，又具有成本效益，因为它建立在从三个大型队列和现有数据中收集的数十年前瞻性数据的基础上。我们的分析将导致 VTE新常见遗传基因座鉴定鉴于危险因素在人口中的高流行率和静脉血栓栓塞的高死亡率，这项工作的潜在公共卫生影响是巨大的。