Data-driven identification of environmental factors in cardiovascular disease

心血管疾病环境因素的数据驱动识别

• 批准号: 8617098
• 负责人: CHIRAG J. PATEL
• 金额: $ 12.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617098
• 关键词: Accounting; Address; Advisory Committees; Air Pollution; Award; Bioinformatics; Biological Markers; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Chlorinated Hydrocarbons; Cholesterol; Chronic Disease; Clinical; Communities; Complex; Coronary heart disease; Data; Diagnosis; Diet; Disease; Doctor of Philosophy; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiologic Methods; Epidemiologic Studies; Epidemiology; Etiology; Event; Future; Gene Expression; Genetic; Genetic Determinism; Genome; Genomics; Goals; Health Surveys; Heart Diseases; Hereditary Disease; Heritability; Human; Hypertension; Infectious Agent; Informatics; Inherited; Investigation; Joints; Knowledge; Measurement; Measures; Mentors; Metabolic; Methodology; Methods; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Patient Self-Report; Pharmacologic Substance; Phase; Phenols; Platelet Factor 4; Prevention; Research; Research Personnel; Research Proposals; Risk; Risk Factors; Role; Scanning; Scientist; Smoking; Technology; Testing; Training; United States; United States National Institutes of Health; Variant; Work; analog; base; cardiovascular disorder risk; cardiovascular risk factor; career development; cohort; community setting; design; disease diagnosis; disorder risk; gene environment interaction; genetic risk factor; genetic variant; genome wide association study; heart disease risk; improved; insulin sensitivity; phthalates; pollutant; population based; prevent; prognostic; public health priorities; public health relevance; statistics; trait

Project Summary/Abstract: The purpose of this award is to provide Chirag Patel, PhD, the support necessary to transition him to an independent investigator studying the environmental and genetic interplay in disease-related traits related to cardiovascular disease (CVD). CVDs, such as coronary heart disease, are among the most burdensome diseases in the United States/world and are multifactorial, arising out of the interplay between environmental and genetic factors. Through Genome-wide Association Studies (GWAS), investigators have been able to associate 1000s of genetic variants with CVD; however identification of environmental factors related to disease has not kept pace. Further, there is a need to describe how environmental and genetic factors interact to ultimately cause CVD. Dr. Patel's long-term research goal is to conduct bioinformatics research to enable inter-disciplinary investigations integrating epidemiology, environmental health sciences, and genomics to identify gene-by- environment interactions that are informative for chronic disease diagnosis and eventual prevention. Dr. Patel has an advanced degree in bioinformatics with significant training in statistics and analysis of genomic data. The career development activities will focus on consolidating and expanding his expertise by 1.) Applying bioinformatics methods to epidemiological data to identify interacting environmental exposures and genetic variants in cardiovascular risk traits, such as blood pressure, 2.) Designing an epidemiological study to ascertain the clinical utility of bioinformatically-derived predictions in their association to future risk for coronary heart disease, and, 3.) Attending courses to expand his knowledge of the environmental health sciences, cardiovascular- and metabolic-related disease genetics, and advanced bioinformatics methodology. An advisory committee, which includes his mentor, Dr. John PA Ioannidis, along with experts in environmental health sciences and bioinformatics (Drs. Stephen A Rappaport and Atul J Butte) will monitor his progress towards independence. The research proposal builds on existing methodological work applying bioinformatics methods in environmental epidemiology, called an "Environment-wide Association Study" (EWAS). EWAS is an analog to the now standard GWAS, implemented to search for environmental factors associated to risk traits and disease. With EWAS, investigators are now able to comprehensively scan personal-level factors such as industrial and consumer-based pollutants, infectious agents, dietary nutrients, and pharmaceuticals for simultaneous association with complex traits. The hypothesis for Dr. Patel's research proposal is that is possible to use data- driven informatics technologies such as EWAS to find environmental factors, and combinations of genetic and environmental factors, associated with CVD quantitative risk factor traits (e.g., blood pressure and cholesterol levels) that describe sizable clinical disease risk. To assess the size of disease risk, Dr. Patel will test whether findings derived from bioinformatics methods can predict clinical CVD events, such as coronary heart disease. In this context, Specific Aim 1 is to identify environmental exposures associated with CVD risk traits, such as blood pressure, using the Environment-Wide Association Study (EWAS) approach. This aim will test whether there are external environmental exposures correlated with CVD risk factors in a community setting. In Specific Aim 2, the candidate will develop an integrative Genetic variant by Environment-Wide Association Study (GxEWAS) approach to identify interacting environmental factors and genetic variants associated with CVD risk traits, including blood pressure and cholesterol levels. The candidate claims that GxEWAS, an integrative approach that combines findings from GWAS and EWAS, will enable identification of synergistic combinations of environmental factors and genetic variants that will describe significant CVD risk trait variability that is currently "missing" in GWAS. In Specific Aim 3, to be executed during the independent R00 phase, Dr. Patel will ascertain the combined risk of environmental and genetic factors on incident coronary heart disease. In Aim 3, the candidate claims that a combination of factors found in EWAS and GWAS will be predictive of clinical heart disease and he will design an epidemiological study to test this hypothesis. To achieve these research aims, Dr. Patel will utilize established NIH- and CDC-sponsored population-based studies, including community-based health surveys and longitudinal cohorts. Dr. Patel will integrate diverse environmental measures, including biomarkers of exposure and self-reported information. The project will enable future R01-level investigation regarding the role of environmental factors in CVD etiology, examining the joint influence of inherited genetic variants and environmental exposures in disease gene expression.

项目摘要/摘要： 这一奖项的目的是为希拉格·帕特尔博士提供必要的支持，使他成为一名 独立调查员，研究环境和遗传在与疾病相关的性状中的相互作用 心血管疾病(CVD)。心血管疾病，如冠心病，是最沉重的负担之一。 美国/世界上的疾病是多因素的，产生于环境因素之间的相互作用 和遗传因素。通过全基因组关联研究(GWAS)，研究人员已经能够 将数以千计的遗传变异与心血管疾病联系起来；然而，与 疾病并没有跟上步伐。此外，还需要描述环境和遗传因素如何相互作用 最终导致心血管疾病。 帕特尔博士的长期研究目标是进行生物信息学研究，以实现跨学科 将流行病学、环境健康科学和基因组学结合起来的研究，以逐个确定基因 为慢性病诊断和最终预防提供信息的环境相互作用。帕特尔博士 拥有生物信息学高级学位，并在基因组数据的统计和分析方面接受过大量培训。 职业发展活动的重点将是巩固和扩大他的专业知识1。施药 用生物信息学方法获得流行病学数据，以确定相互作用的环境暴露和基因 心血管风险特征的变异，如血压，2。)设计一项流行病学研究以 确定生物信息衍生的预测在其与冠状动脉未来风险之间的临床实用性 心脏病，以及3.)参加课程以扩大他在环境健康科学方面的知识， 心血管和代谢相关疾病遗传学，以及先进的生物信息学方法。一个 顾问委员会，成员包括他的导师John PA Ioannidis博士和环境专家 健康科学和生物信息学(史蒂芬·A·拉帕波特博士和阿图尔·J·巴特博士)将监督他的进展 走向独立。 该研究建议建立在应用生物信息学方法的现有方法学工作的基础上 环境流行病学，称为“全环境协会研究”(Ewas)。Ewas是类似于 现在的标准GWAs，用于寻找与风险特征和疾病相关的环境因素。 有了Ewas，调查人员现在能够全面扫描个人层面的因素，如工业和 以消费者为基础的污染物、感染剂、饮食营养素和药物 与复杂的特征相联系。帕特尔博士的研究提议的假设是，有可能使用数据- 被驱动的信息学技术，如Ewas，以发现环境因素，以及遗传和 与心血管疾病量化风险因素特征相关的环境因素(例如，血压和胆固醇 水平)，描述了相当大的临床疾病风险。为了评估疾病风险的大小，帕特尔博士将测试 来自生物信息学方法的研究结果可以预测临床心血管事件，如冠心病。 在这方面，具体目标1是确定与心血管疾病风险特征有关的环境暴露，例如 血压，使用全环境协会研究(EWAS)方法。这一目标将检验是否 在社区环境中，存在与心血管疾病风险因素相关的外部环境暴露。具体而言 目标2，候选人将通过全环境关联研究开发出一种整合的基因变体 (GxEwas)方法识别与心血管疾病相关的相互作用的环境因素和遗传变异 风险特征，包括血压和胆固醇水平。候选人声称，GxEwas，一个综合性的 结合GWAS和EWAS的调查结果的方法将能够识别协同组合 环境因素和遗传变异将描述显著的心血管疾病风险特征变异性，即 目前在GWA中“失踪”。在具体目标3中，将在独立的R00阶段执行，Patel博士 将确定环境和遗传因素对冠心病事件的综合风险。在……里面 目标3，候选人声称，在EWAS和GWAS中发现的因素组合将预测 他将设计一项流行病学研究来验证这一假设。 为了实现这些研究目标，帕特尔博士将利用美国国立卫生研究院和美国疾病控制与预防中心建立的以人口为基础的 研究，包括基于社区的健康调查和纵向队列。帕特尔博士将整合不同的 环境措施，包括暴露的生物标志物和自我报告的信息。该项目将 启用未来R01级别的关于环境因素在心血管疾病病因中的作用的调查，检查 遗传变异和环境暴露对疾病基因表达的联合影响。