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（T2 DM） 在美国退伍军人中非常普遍，是心脏、血管和 肝脏疾病我们已经组建了一个多学科的研究团队，来自多个VA和学术医学 心血管和代谢疾病、临床和流行病学研究、EHR等专业中心 基于研究方法，遗传流行病学和统计遗传学，参加百万退伍军人 计划（MVP）通过β测试奖，题为“遗传学的心脏代谢疾病在弗吉尼亚州 人口”。此外，我们还帮助建立了一个高度协同的网络， 工作组促进了几个受资助的Beta测试团队之间的合作项目。由于第一 不到18个月前，我们在GenISIS中获得了MVP遗传和表型数据， 基本上或导致已经证实和/或鉴定了>500个体重指数易感基因座的研究， 身高、糖尿病前期、T2 D、血脂异常、非酒精性脂肪性肝病（NAFLD）、冠状动脉疾病 (CAD)和外周动脉疾病（PAD）。我们已经向科学界公布了我们的发现 在国家会议上作了超过20次发言，并已提交或正准备提交多份报告， 与这些初步努力有关的手稿。对于目前的续期申请，我们建议延续这条线 研究重点是利用与疾病时间进程相关的纵向信息。在 目标1，我们将建立在我们最初的基因组全关联研究（GWAS）的势头， 疾病和单时间点措施的数量性状，通过扩大我们的努力，检查遗传 心脏代谢特征纵向进展的基础，包括BMI增加;糖尿病前期至2型 糖尿病，T2 D中微血管和大血管并发症的表现，NAFLD到肝硬化和癌症， CHD、PAD和腹主动脉瘤（AAA）疾病的临床前状况。在目标2中，我们将探索 多个心脏代谢性状以及与非心脏代谢性状之间的多效性关系， MVP和英国生物样本库此外，我们将进行参与者水平的孟德尔随机化研究， 更有力地证明了通过多效性识别的高度相关的性状对之间的因果联系， 分析。最后，在目标3中，我们将评估衍生的多基因风险评分的区分能力， VA人群中的心脏代谢疾病，特别强调评估其在不同 少数民族人口。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/或生活方式因素的相互作用将提供更精确的 了解疾病随时间的进展，从而为基于更有针对性的基因组医学提供信息。 疾病管理贯穿于退伍军人的一生。