Genetics of Cardiometabolic Diseases in the VA Population

心脏代谢紊乱包括肥胖、胰岛素抵抗、相关的血脂异常和2型糖尿病(T2 DM) 在美国退伍军人中非常普遍，是心脏、血管和心脏发育的主要因素 肝脏疾病。我们已经组建了一支由多个退伍军人管理局和学术医学组成的多学科研究团队 在心血管和代谢性疾病、临床和流行病学研究、EHR方面拥有专业知识的中心 基于研究方法，遗传流行病学，统计遗传学，参与百万老兵 项目(MVP)通过Beta-TEST奖，题为“退伍军人心脏代谢性疾病的遗传学” 人口“。此外，我们还帮助建立了一个基于特征和方法高度协同的网络 工作组促进了几个受资助的Beta测试团队之间的协作项目。自第一次 不到18个月前，我们在GenISIS中获得了MVP基因和表型数据，我们做出了贡献 基本上参与或领导了已经确认和/或确定了体重指数易感基因的研究， 身高、糖尿病前期、T2D、血脂异常、非酒精性脂肪肝(NAFLD)、冠状动脉疾病 (CAD)和外周动脉疾病(PAD)。我们已经向科学界传播了我们的发现 通过&gt；20次在全国会议上的发言，并已经或准备提交 与这些最初的努力有关的手稿。对于目前的续期申请，我们建议继续这条线 调查的重点是利用与病程有关的纵向信息。在……里面 目标1，我们将在我们最初的流行的全基因组关联研究(GWAS)的势头基础上 疾病和数量性状的单时间点测量通过扩大我们的努力来检查基因 心脏代谢特征纵向进展的基础，包括BMI增加；糖尿病前期到2型 糖尿病，T2D的微血管和大血管并发症的表现，NAFLD到肝硬变和癌症， 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 多种心脏代谢性状之间以及与非心脏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别的孟德尔随机化研究，以 更有力地记录了通过我们的多效性确定的高度相关的特征对之间的因果联系 分析。最后，在目标3中，我们将评估派生的多基因风险分数对 退伍军人中的心脏代谢性疾病，特别强调评估它们在不同疾病中的价值 少数族裔人口。我们的首要假设是，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准确的 了解疾病随时间的发展，从而为更有针对性的基因组医学提供信息 在退伍军人的整个生命过程中进行疾病管理。

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.