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（例如血压（BP）和血浆脂质）的管理仍然是一个重大的公共卫生问题。因此，了解这些特征的遗传基础以及环境如何调节影响这些特征的遗传效应很重要，因为它可能为干预措施提供重要的线索。在过去的几年中，全基因组关联研究（GWAS）的出现在识别数百种与许多常见的复杂疾病和疾病相关性状有关的常见遗传变异方面的迅速发展彻底改变了该领域。尽管取得了这些非凡的成就，但大多数确定的遗传变异的影响较小，赋予了相对较小的风险增加，并且在大多数情况下仅解释了特征方差的较小比例。人们越来越认识到，对共同变异的主要影响（通常具有较小的影响）的近乎排他性的关注已成为鉴定这些疾病特征的其他基因（具有较大效果）的障碍。这些发现工作需要更复杂的方法，例如基因环境相互作用，对相关性状的多效影响的分析以及途径分析。 尽管文献中已经报道了涉及基因环境相互作用的重要研究，但这是使用非常大的样本量系统地评估基因生活方式相互作用的第一个系统的大型财团级努力。我们建议研究基因 - 叶片相互作用，与多效性分析相关性状的遗传结构和途径分析，每种都作为揭示更多BP和脂质中无法解释的无法解释的遗传方差的手段。我们将通过利用具有表型，相关的生活方式数据和密集的共同基因型数据（GWAS）以及稀有变体（Exome Chip）的现有多民族研究/同类群体的非凡资源来做到这一点。我们的申请涉及25个人群，其中包括90,673名欧洲人，34,543名非裔美国人，13,174名西班牙裔美国人和12,375个亚洲人的GWAS数据，总计n = 150,765，n = 150,765，样品中约有61％。将寻求两个大型联盟的复制，其总样本量为160,958名受试者（全球BP遗传学或GBPGEN，以及全球脂质遗传学财团或GLGC）。这将代表迄今为止最重要的努力，以调查发现或复制的总样本量超过300,000的相互作用。及时的资金可以通过将这一应用程序组合在一起来维持产生的巨大动力，这最终可能导致新颖的治疗方法，从而可能影响临床实践。