A Multi-Ancestry Study of Gene-Lifestyle Interactions and Multi-Omics in Cardiometabolic Traits

基因-生活方式相互作用和心脏代谢特征多组学的多祖先研究

• 批准号: 10398246
• 负责人: DABEERU C RAO
• 金额: $ 220.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-27 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398246
• 关键词: Accounting; Affect; African; African ancestry; Alcohol consumption; Architecture; Asian; Asian ancestry; Biological; Blood Pressure; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cigarette; Clinical; Collaborations; Complex; Coronary heart disease; DNA Methylation; Data; Detection; Development; Diabetes Mellitus; Dyslipidemias; Ensure; Environment; European; Evaluation; Exhibits; Foundations; Freedom; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Risk; Genomics; Goals; Health; Hispanic; Hispanic ancestry; Homeostasis; Hypertension; Individual; Intervention; Investigation; Japan; Joints; Lead; Life Style; Lipids; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Multiomic Data; Multivariate Analysis; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Pathway Analysis; Pathway interactions; Physical activity; Population; Population Heterogeneity; Precision Medicine Initiative; Prevention; Psychosocial Factor; Public Health; Research; Research Personnel; Risk; Risk Factors; Sample Size; Sampling; Sampling Studies; Series; Site; Sleep; Smoking; Stroke; Study of Latinos; Testing; Therapeutic; Trans-Omics for Precision Medicine; Variant; Veterans; base; biobank; blood lipid; burden of illness; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; clinical practice; clinically relevant; gene environment interaction; genome wide association study; genome-wide; genomic locus; health disparity; improved; insight; lifestyle factors; modifiable risk; molecular phenotype; multiple omics; novel; novel diagnostics; novel therapeutics; personalized care; pleiotropism; programs; sex; tool; trait; working group

PROJECT SUMMAR/ABSTRACT Cardiometabolic diseases and risk factors, including hypertension, dyslipidemia, adiposity, and type 2 diabetes, represent a major public health burden that disproportionately affects diverse (non-European ancestry) populations. Cardiometabolic traits are influenced by both genetic and environmental (lifestyle) factors. Therefore, understanding interactions (GxE) between these factors could provide insights into intervention, prevention and therapeutic strategies to reduce the burden of disease. Many genome-wide association studies (GWAS) have made important genetic discoveries for many complex traits through approaches based on “genetic main effects”. However, genome-wide interaction studies (GWIS) are still limited. The objective of this study is therefore to identify novel genetic loci associated with cardiometabolic traits through GWIS in large samples, to investigate gene-lifestyle interactions in the cardiometabolic trait loci, and to characterize the molecular effects underlying the interactions by leveraging existing “Omics” data such as DNA methylation, gene expression, and metabolites. By investigating genomic and lifestyle contributors to health outcomes through their interactions across diverse populations and between sexes, our proposal reflects the priorities of the Precision Medicine Initiative (PMI) whose focus is the interplay between lifestyle/environment and genetics, with an emphasis on diverse populations. We propose to evaluate gene-lifestyle interactions across diverse populations (European, African, Hispanic, and Asian). Our recent progress with blood pressure, lipids, and dichotomized lifestyle factors (smoking, alcohol consumption, physical activity, educational attainment, psychosocial factors, and sleep) encountered limited statistical power. Therefore, we propose to vastly increase the power for GWIS with an ~10-fold larger sample size and expand our focus to include other cardiometabolic traits (adiposity and diabetes traits), quantitative lifestyle exposures (e.g., cigarettes per day), and aggregate Lifestyle Risk Scores as an overall lifestyle risk factor for cardiometabolic health; evaluate the impact of identified interactions on clinical endpoints (like coronary heart disease); assess the druggability of identified interactions; and characterize interactions using multiple omics data. Our proposal includes our recent discovery studies (N~130,000), our recent replication studies (N~252,000), and the addition of several new, substantially larger studies including the Million Veteran Program (N~234,000), the UK Biobank (N~478,000), the Biobank Japan (N~160,000), and the Study of Latinos (N~13,000), among others. The overall sample, including 912,000 European, 91,000 African, 33,000 Hispanic, and 231,000 Asian ancestry individuals, represents the most significant effort to date to investigate interactions with an aggregate sample size of about 1.267 million. Findings can lead to new diagnostic and therapeutic tools, contribute to precision care in the management of cardiometabolic disorders, and provide insights for the PMI with the ultimate goal of enhancing clinical practice.

项目摘要/摘要 心脏代谢疾病和危险因素，包括高血压，血脂异常，肥胖和类型2 糖尿病代表着一种严重的公共卫生烧伤，对多种多样的影响不成比例（非欧洲） 祖先）人口。心脏代谢性状受遗传和环境（生活方式）的影响 因素。因此，了解这些因素之间的相互作用（GXE）可以为您提供见解 干预，预防和理论策略减少疾病的燃烧。许多全基因组 协会研究（GWAS）通过 基于“遗传主要影响”的方法。但是，全基因组相互作用研究（GWIS）仍然是 有限的。因此，这项研究的目的是确定与心脏代谢相关的新遗传位置 通过大型样本中的GWIS特征，研究心脏代谢性状基因座中的基因相互作用， 并通过利用现有的“ OMIC”数据来表征相互作用的分子效应 作为DNA甲基化，基因表达和代谢产物。通过调查基因组和生活方式的贡献者 我们的提议通过在潜水员人群之间以及性别之间的互动来实现健康成果 反映了Precision Medicine Initiative（PMI）的重点，该计划的重点是 生活方式/环境和遗传学，重点是潜水员人群。 我们建议评估潜水员种群（欧洲，非洲，西班牙裔， 和亚洲）。我们最近在血压，脂质和二分法的生活方式因素方面进展（吸烟， 遇到饮酒，体育锻炼，教育程度，社会心理因素和睡眠） 有限的统计能力。因此，我们建议大大增加大约10倍大的GWIS的能力 样本量并将我们的重点扩展到包括其他心脏代谢性状（肥胖和糖尿病特征）， 定量生活方式暴露（例如每天香烟），并将生活方式风险分数汇总为总体 心脏代谢健康的生活方式风险因素；评估确定的相互作用对临床终点的影响 （例如冠心病）；评估已确定相互作用的可药用性；并表征互动 使用多个OMICS数据。我们的建议包括我们最近的发现研究（N〜130,000），我们最近 复制研究（n〜252,000），并添加了几项新的，更大的研究，包括 百万退伍军人计划（N〜234,000），英国生物银行（N〜478,000），日本生物库（N〜160,000）和 拉丁美洲人的研究（N〜13,000）等。总体样本，包括912,000欧洲，91,000非洲人 33,000个西班牙裔和231,000个亚洲血统人物代表了迄今为止最重要的努力 调查与总样本量约12.67亿的相互作用。发现可能导致新 诊断和治疗工具，有助于心脏代谢疾病管理的精确护理， 并提供PMI的见解，其最终目标是增强临床实践。