A Multi-Ethnic Study of Gene-Lifestyle Interactions in Cardiovascular Traits

心血管特征中基因与生活方式相互作用的多种族研究

• 批准号: 9197332
• 负责人: DABEERU C RAO
• 金额: $ 204.22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197332
• 关键词: Address; African American; Aging; Alcohol consumption; American; Architecture; Asians; Blood Pressure; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Caring; Cohort Studies; Collaborations; Complex; Complex Genetic Trait; Coronary Arteriosclerosis; Coronary artery; Data; Diet; Disease; Disease Management; Dyslipidemias; Educational Background; Environment; Essential Hypertension; European; Funding; Genes; Genetic; Genome; Genotype; Goals; Guidelines; Heart; Heart Diseases; Heritability; Hispanic Americans; Hypertension; Individual; International; Intervention; Investigation; Joints; Kidney Diseases; Lead; Life Style; Lipids; Literature; Mediating; Modeling; Pathway Analysis; Pathway interactions; Phenotype; Physical activity; Plasma; Public Health; Reporting; Research; Research Infrastructure; Resources; Risk; Risk Factors; Sample Size; Sampling; Smoking; Socioeconomic Status; Statistical Methods; Stroke; Time; Variant; Work; blood lipid; cardiovascular risk factor; clinical practice; cohort; exome; gene environment interaction; genetic epidemiology; genetic variant; genome wide association study; lifestyle data; novel; novel therapeutic intervention; pleiotropism; public health relevance; rare variant; sobriety; trait; working group

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) and management of its risk factors such as blood pressure (BP) and plasma lipids continue to be a major public health problem. Therefore, understanding the genetic basis of these traits and how the environment modulates genetic effects in influencing these traits is important because it may provide important clues for interventions. Over the past several years, the advent of Genome-Wide Association Studies (GWAS) has revolutionized the field with rapid progress in identifying hundreds of common genetic variants associated with many common complex diseases and disease-related traits including cardiovascular traits. Despite these extraordinary accomplishments, most of the identified genetic variants have small effect sizes, confer relatively small increments of risk and, for the most part, explain only small proportions of the trait variance. It is increasingly recognized that the near-exclusive focus on main effects of common variants (which generally have small effects) has become a barrier to the identification of additional genes (with larger effects) underlying these disease traits. These discovery efforts need more sophisticated approaches such as gene- environment interactions, analysis of pleiotropic effects on correlated traits, and pathway analysis. Although important research involving gene-environment interactions is being reported in the literature, this is the first systematic, well-powered large consortium-level effort for systematically evaluating gene- lifestyle interactions using very large sample sizes. We propose to investigate gene-lifestyle interactions, the genetic architecture of correlated traits with pleiotropy analysis, and pathway analysis, each as a means for uncovering more of the unexplained genetic variance in BP and lipids. We will do this by leveraging the extraordinary resources of existing multi-ethnic studies/cohorts that have the phenotypes, relevant lifestyle data and dense genotype data on common (GWAS) as well as rare variants (Exome chip). Our application involves 25 cohorts with GWAS data on 90,673 European Americans, 34,543 African Americans, 13,174 Hispanic Americans, and 12,375 Asians, for an overall total of N=150,765, with Exome Chip data on about 61% of the samples. Replication will be sought from two large consortia with an aggregate sample size of 160,958 subjects (Global BP Genetics or GBPgen, and Global Lipids Genetics Consortium or GLGC). This would represent the most significant effort to date to investigate interactions with an aggregate sample size over 300,000 in either discovery or replication. Timely funding can sustain the great momentum generated by putting together this application, which could ultimately lead to novel therapeutic approaches thus potentially impacting clinical practice.

描述（由申请人提供）：心血管疾病（CVD）及其危险因素（如血压（BP）和血脂）的管理仍然是一个主要的公共卫生问题。因此，了解这些性状的遗传基础以及环境如何调节影响这些性状的遗传效应是很重要的，因为它可能为干预提供重要线索。在过去的几年中，全基因组关联研究（GWAS）的出现彻底改变了该领域，在识别与许多常见复杂疾病和疾病相关特征（包括心血管特征）相关的数百种常见遗传变异方面取得了快速进展。尽管取得了这些非凡的成就，但大多数已确定的遗传变异的影响规模很小，带来的风险增量相对较小，而且在大多数情况下，只能解释性状变异的一小部分。越来越多的人认识到，几乎只关注常见变异的主要影响（通常影响很小）已经成为鉴定这些疾病特征背后的其他基因（影响较大）的障碍。这些发现工作需要更复杂的方法，如基因-环境相互作用，对相关性状的多效效应分析和途径分析。虽然文献中已经报道了涉及基因-环境相互作用的重要研究，但这是第一次系统的、强有力的大型联盟级努力，使用非常大的样本量来系统地评估基因-生活方式相互作用。我们建议研究基因与生活方式的相互作用，相关性状的遗传结构与多效性分析，以及途径分析，每一个都可以作为揭示更多未解释的BP和血脂遗传变异的手段。我们将利用现有的多种族研究/队列的非凡资源，这些研究/队列拥有常见（GWAS）和罕见变体（外显子组芯片）的表型、相关生活方式数据和密集的基因型数据。我们的应用程序涉及25个队列，其中有90,673名欧洲美国人，34,543名非洲美国人，13,174名西班牙裔美国人和12,375名亚洲人的GWAS数据，总N=150,765，其中约61%的样本有Exome Chip数据。将从两个总样本量为160,958名受试者的大型联盟（Global BP Genetics或GBPgen和Global Lipids Genetics Consortium或GLGC）中寻求复制。这将是迄今为止在研究发现或复制的总样本量超过30万的相互作用方面所做的最重要的努力。及时的资助可以维持这一应用程序所产生的巨大势头，这可能最终导致新的治疗方法，从而潜在地影响临床实践。