Genetics of Cardiometabolic Diseases in the VA Population

VA 人群心脏代谢疾病的遗传学

• 批准号: 10516086
• 负责人: Kyong-Mi Chang
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516086
• 关键词: Abdominal Aortic Aneurysm; Academic Medical Centers; Address; Amputation; Award; Biological Markers; Body mass index; Cardiometabolic Disease; Cardiovascular Diseases; Clinical; Clinical Research; Clinical effectiveness; Communities; Coronary Arteriosclerosis; Cross-Sectional Studies; Data; Development; Disease; Disease Management; Disease Progression; Dyslipidemias; EHR research; Electronic Health Record; Enrollment; Environment; Environmental Risk Factor; Family; Funding; Genetic; Genetic Determinism; Genetic Risk; Genomic medicine; Genomics; Goals; Growth; Health; Healthcare Systems; Heart Diseases; Heart failure; Height; Information Systems; Insulin Resistance; Interdisciplinary Study; Investigation; Life Style; Link; Lipids; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Manuscripts; Measures; Medical center; Mendelian randomization; Metabolic Diseases; Methodology; Methods; Minority Groups; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Peripheral arterial disease; Phenotype; Population; Prediabetes syndrome; Publishing; Rare Diseases; Research Methodology; Research Personnel; Risk Factors; Risk Management; Safety; Science; Susceptibility Gene; Testing; Therapeutic Intervention; Time; Vascular Diseases; Veterans; biobank; cardiometabolism; clinical risk; clinically relevant; cohort; cooperative study; epidemiology study; experience; genetic epidemiology; genome wide association study; improved; insight; lifestyle factors; macrovascular disease; meetings; non-alcoholic fatty liver disease; novel; phenotypic data; phenotyping algorithm; pleiotropism; polygenic risk score; pre-clinical; programs; prospective; risk prediction; risk prediction model; risk variant; therapeutic target; trait; web platform; working group

Cardiometabolic disorders including obesity, insulin resistance, related dyslipidemia, and type 2 diabetes (T2DM) are highly prevalent among U.S. Veterans and serve as major factors in the development of heart, vascular and liver diseases. We have assembled a multi-disciplinary research team from multiple VA and academic medical centers with expertise in cardiovascular and metabolic disease, clinical and epidemiological research, EHR based research methods, genetic epidemiology, and statistical genetics, to participate in the Million Veteran Program (MVP) through the Beta-test award entitled “Genetics of Cardiometabolic Diseases in the VA Population”. In addition, we have helped establish a highly synergistic network of trait- and methodology-based Working Groups that have facilitated collaborative projects among several funded Beta-test teams. Since first gaining access to MVP genetic and phenotypic data in GenISIS less than 18 months ago, we have contributed substantially to or led studies that have confirmed and/or identified >500 susceptibility loci for body mass index, height, prediabetes, T2D, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), coronary artery disease (CAD), and peripheral artery disease (PAD). We have disseminated our findings to the scientific community through >20 presentations at national meetings and have submitted or are preparing to submit multiple manuscripts related to these initial efforts. For the current renewal application, we propose to continue this line of investigation with particular focus in leveraging longitudinal information related to time course of disease. In Aim 1, we will build on our momentum of our initial genome wide association studies (GWAS) of prevalent disease and single time point measures of quantitative traits by expanding our efforts to examine the genetic basis of the longitudinal progression of cardiometabolic traits including increasing BMI; pre-diabetes to type 2 diabetes, manifestation of micro- and macro-vascular complications in T2D, NAFLD to liver cirrhosis and cancer, pre-clinical conditions to CHD, PAD, and abdominal aortic aneurysm (AAA) disease. In Aim 2, we will explore the pleiotropic relationships between multiple cardiometabolic traits as well as with non-cardiometabolic traits in the MVP and the UK Biobank. Moreover, we will conduct participant-level Mendelian Randomization studies to more robustly document causal links between highly correlated pairs of traits identified through our pleiotropy analyses. Finally, in Aim 3, we will assess the discriminatory power of derived polygenic risk scores for cardiometabolic diseases in the VA population, with specific emphasis upon evaluating their value in different minority populations. Our overarching hypothesis is that elucidating the genetic underpinnings of cardiometabolic conditions and their interactions with environmental and/or lifestyle factors will provide a more precise understanding of disease progression over time, thereby informing more targeted genomic medicine-based disease management throughout the course of Veterans' lives.

心脏代谢疾病，包括肥胖，胰岛素抵抗，相关血脂异常和2型糖尿病（T2DM） 在美国退伍军人中非常普遍，是心脏发展，血管和 肝病。我们已经组建了来自多个VA和学术医学的多学科研究团队 具有心血管和代谢疾病，临床和流行病学研究的专业知识的中心，EHR 基于研究方法，遗传流行病学和统计遗传学，参与百万退伍军人 通过beta检验奖的计划（MVP），标题为“ VA中的心脏代谢疾病的遗传学 人口。 在几个资助的Beta测试团队中准备了合作项目的工作组。自第一次 在不到18个月前，获得Genisis中MVP遗传和表型数据的访问，我们贡献了 基本上或已确认和/或确定> 500个体重指数的易感性位置的研究或LED研究 身高，糖尿病前，T2D，血脂异常，非酒精性脂肪肝病（NAFLD），冠状动脉疾病 （CAD）和周围动脉疾病（PAD）。我们已经将我们的发现传播给科学界 通过在全国会议上进行20个演讲，并已提交或准备提交多个 手稿与这些最初的努力有关。对于当前的续订应用程序，我们建议继续此行 投资特别重点，以利用与疾病时间过程有关的纵向信息。在 AIM 1，我们将基于我们最初的基因组广泛关联研究（GWAS）的势头 通过扩大我们检查遗传的努力，疾病和单个时间点测量 心脏代谢性状的纵向进展的基础，包括增加BMI； 2型前糖尿病 糖尿病，T2D中微血管并发症的糖尿病，NAFLD对肝肝硬化和癌症的表现， CHD，PAD和腹主动脉瘤（AAA）疾病的临床前疾病。在AIM 2中，我们将探索 多种心脏代谢性状以及非核代谢性状之间的多效性关系 MVP和英国生物库。此外，我们将进行参与者级的孟德尔随机研究 更牢固地记录了通过我们的多效性鉴定的高度相关性状对之间的因果关系 分析。最后，在AIM 3中，我们将评估派生多基因风险评分的歧视能力 VA人群中的心脏代谢疾病，特别强调评估其价值 少数群体。我们的总体假设是阐明心脏代谢的遗传基础 条件及其与环境和/或生活方式因素的互动将提供更精确的 了解疾病随着时间的推移的了解，从而告知更多基于基因组医学 在退伍军人生活过程中，疾病管理。