Genetic and Environmental Risk Factors for Venous Thromboembolism

描述(申请人提供)：背景：静脉血栓栓塞症(VTE)每年有1-2/1000美国人发病，是心血管死亡的常见原因。静脉血栓栓塞症的病因是多因素的，遗传和环境因素共同作用于发病。然而，已知的遗传和环境风险因素解释了不到50%的VTE发病率，全基因组关联研究(GWAS)在识别新的基因座方面一直不成功。人们对可能的基因-环境相互作用知之甚少。设置：此 这项研究将由哈佛大学和梅奥诊所的一个经验丰富的、多学科、多机构的血栓栓塞症研究人员、遗传和心血管流行病学家以及统计遗传学专家进行。该项目的研究人员拥有数十年进行遗传和流行病学研究的经验，并发表了数百篇与当前提案相关的同行评议论文。研究计划：我们将检查护士健康研究I&II(NHS I&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，对象为121,700名和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。我们将使用最新推出的Illumina(R)Human Exome珠芯片对2,500例静脉血栓形成患者和2,500名对照进行第一次外显子组广泛关联研究，该芯片包括220,000个编码遗传变异，人群患病率为0.005%。我们将在梅奥诊所的2000例静脉血栓栓塞症患者和2000例对照的独立临床样本中复制我们的最新发现。此外，我们将在外显子芯片上包括定制内容，以对之前完成的两个VTE GWA中发现的前5,000个单核苷酸多态(SNPs)进行深度复制。最后，我们将研究已证实的基因多态与我们先前工作中确定的四个VTE关键环境危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。与公共卫生相关：静脉血栓栓塞症是一种常见且致命的疾病，美国代理卫生局局长强调了这一事实，他在2008年发布了一份名为《预防深静脉血栓和肺栓塞症的行动号召》，敦促“对深静脉血栓形成的原因、预防和治疗进行更多研究”。目前的提案将是迄今为止对VTE的遗传和环境风险因素进行的最全面的评估，将提供对VTE的基本病理生理学的洞察，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数十年预期数据的基础上。我们的分析将导致 静脉血栓栓塞症新常见遗传基因座的鉴定。鉴于危险因素在人群中的高患病率和VTE的高死亡率，这项工作对公众健康的潜在影响是巨大的。

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.