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

基本信息

批准号：
8630851
负责人：
Ingrid Bernadette Borecki
金额：
$ 216.94万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630851
关键词：
Address African American Aging Alcohol consumption American Architecture Asians Blood Pressure Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cohort Studies Collaborations Complex Complex Genetic Trait Coronary Arteriosclerosis 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 Variant Work base cardiovascular risk factor clinical practice cohort exome gene environment interaction genetic epidemiology genetic variant genome wide association study novel novel therapeutic intervention pleiotropism public health relevance rare variant sobriety trait working group

项目摘要

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遗传效应来影响这些性状非常重要，因为它可能为干预措施提供重要线索。在过去的几年里，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，但大多数已识别的遗传变异的效应较小，带来的风险增量相对较小，并且在很大程度上只能解释一小部分性状变异。人们越来越认识到，几乎完全关注常见变异的主要影响（通常影响较小）已成为识别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，例如基因-环境相互作用、对相关性状的多效性分析以及途径分析。尽管文献中报道了涉及基因-环境相互作用的重要研究，但这是第一个系统性的、强有力的大型联盟级别的努力，使用非常大的样本量系统地评估基因-生活方式的相互作用。我们建议通过多效性分析和通路分析来研究基因与生活方式的相互作用、相关性状的遗传结构，每一项都作为揭示更多无法解释的血压和血脂遗传变异的手段。我们将利用现有多种族研究/队列的非凡资源来实现这一目标，这些研究/队列具有表型、相关生活方式数据以及常见变异（GWAS）和罕见变异（外显子组芯片）的密集基因型数据。我们的应用程序涉及 25 个队列，其中包含 90,673 名欧洲裔美国人、34,543 名非裔美国人、13,174 名西班牙裔美国人和 12,375 名亚洲人的 GWAS 数据，总共 N=150,765，外显子组芯片数据涉及约 61% 的样本。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）寻求复制。这将代表迄今为止在发现或复制方面调查与超过 300,000 个总样本量的相互作用的最重大努力。及时的资助可以维持该应用程序产生的巨大动力，最终可能会产生新的治疗方法，从而可能影响临床实践。