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（由申请人提供）：背景：静脉血栓栓塞（VTE）每年1-2/1000美国人，是心血管死亡的常见原因。 VTE的病因是多因素的，遗传和环境因素都导致发病率。然而，已知的遗传和环境风险因素解释了少于50％的VTE发生率和全基因组关联研究（GWAS）在识别新基因座方面没有成功。关于可能的基因环境相互作用知之甚少。设置：这个 研究将由经验丰富的，多学科的，多机构的血栓栓塞研究人员，遗传和心血管流行病学家，以及在哈佛大学和梅奥诊所工作的统计遗传学专家。该项目的研究人员拥有数十年来进行遗传和流行病学研究的经验，并发表了数百份与当前建议相关的同行评审。研究计划：我们将研究护士健康研究I＆II（NHS I＆II）的数据，以及卫生专业人员随后的研究（HPFS）研究。 NHS I＆II和HPF正在进行的121,700和116,686名女护士和51,529名男性卫生专业人员的前瞻性队列研究。对于这三个队列中的每一个，都收集了描述VTE和前瞻性环境暴露的数据超过25年。我们将使用新近可用的Illumina（R）Humananexome Beadchip进行2,500例VTE病例和2,500个对照中的VTE的首次外显着关联研究（XWA），其中包括220,000个编码遗传变异，以达到0.005％的人群流行。我们将在Mayo Clinic的2000 VTE病例和2000个对照的基于独立的诊所样本中复制我们的顶级XWA发现。此外，我们将在外来芯片上包括自定义内容，以对在两个先前完成的VTE GWAS中鉴定出的前5,000个单核苷酸多态性（SNP）进行深层复制。最后，我们将研究确认的遗传多态性和四个关键的环境风险因素之间在我们先前的工作中确定的VTE：肥胖，身体不活动，吸烟和绝经后激素的使用。与公共卫生有关：VTE是一种常见且致命的疾病，这一事实是由美国代理外科医生强调的，2008年在2008年发出了“采取行动呼吁，以防止深静脉血栓形成和肺栓塞'敦促”敦促对原因，预防和深层静脉势不足的治疗进行更多研究。”当前的提案将是对VTE迄今为止对VTE的遗传和环境风险因素的最全面评估，它将深入了解VTE的基本病理生理学，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，因为它是基于从三个大型同类人群和现有数据收集的几十年收集数据。我们的分析将导致 鉴定VTE的新型常见遗传基因座。鉴于危险因素的人口较高和VTE的死亡率高，这项工作的潜在公共卫生影响很大。