Cardiovascular Disease Risk Factors, Prevalent Cardiovascular Disease, and Genetics in the Million Veteran Program

 描述(由申请人提供)： 心血管疾病(CVD)风险评估的重点是白人根据年龄、性别、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、糖尿病、吸烟和血压(BP)信息进行的门诊数据。在全基因组关联研究中，风险因素(RF)和总体心血管疾病风险与遗传变异相关，表型主要基于使用Framingham方法的单个RF测量。以前的研究主要集中在欧洲裔美国人(EA)，一般没有包括退伍军人。关于非裔美国人(AA)或西班牙裔美国人(HA)的心血管疾病危险因素基因的信息很少，这两个群体在退伍军人事务部中非常重要。随着百万退伍军人计划(MVP)队列的推出，我们有了一个独特的机会来研究这些亚群中的基因和心血管疾病风险。到目前为止，还没有开发出将MVP问卷和基因数据与退伍军人的电子医疗信息联系起来的方法。我们建议使用MVP队列，通过关注多种族、罕见变异和先天风险因素水平来解决科学差距。在拟议的研究中，我们首先通过开发方法来创建虚拟基线检查，以使用系统的方法将MVP基线检查的数据链接到VA电子健康记录。退伍军人的结果受到美国地理区域、种族/民族、门诊就诊频率和其他变量的影响。基于我们处理MVP问卷数据和电子医疗数据的系统方法，我们评估了常见和罕见等位基因与CVD RFS因果路径中基因组范围的关联，并考虑了环境(饮食质量、药物治疗)以及对当前和以前的RF水平的评估。方法包括在MVP基线就诊时使用Willett食物频率问卷测量单个退伍军人管理局门诊患者在饮食质量调整和不调整饮食质量的情况下测量定量心血管RFS(低密度脂蛋白-C、非高密度脂蛋白-C、甘油三酯、体重指数)。其他方法包括对心血管疾病RFS进行药物治疗以得出推定的未经治疗的RF水平，以及在MVP基线就诊前5年和10年内在VA门诊就诊时测量先前定量的CVD RFS，当这些数据可用时。我们将进行常见的变异关联研究(CVA)和罕见的变异关联研究(RVA)，测试基因变异与a)流行的冠心病(CHD)[心肌梗死、冠状动脉旁路移植术(CABG)病史、经皮冠状动脉介入治疗(PCI)病史]和b)流行的动脉粥样硬化性血栓形成史之间的关联，并比较不同种族和民族的影响，以及c)使用种族内部和跨种族验证的CVD相关SNP的遗传风险评分(GRS)来检查CHD和中风的多基因关联。该项目将为未来退伍军人管理局的MVP参与者提供一个心血管事件分析的平台。此外，拟议的研究结果将允许比较基因变异对心脏代谢RFS危险因素的影响以及AA、HA和EA退伍军人中动脉粥样硬化性疾病的患病率。心血管疾病给退伍军人造成了极大的医疗负担。该项目将调查不同民族和种族的MVP参与者中心血管疾病风险因素的遗传和环境决定因素的作用。

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) risk estimation has focused on outpatient data from whites according to age, sex, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), diabetes, smoking, and blood pressure (BP) information. Risk factors (RFs) and overall CVD risk are associated with genetic variations in genome-wide association studies (GWAS), and phenotypes have largely been based on single RF measurements using a Framingham approach. Previous research has focused on European Americans (EA), and generally has not included Veterans. There is little information on CVD risk factor genes in African Americans (AA) or Hispanic Americans (HA), two population groups that are extremely important in the VA. With the availability of the Million Veteran Program (MVP) cohort, we have a unique opportunity to study genes and CVD risk among these subgroups. Up to now methods have not been developed to link MVP questionnaire and genetic data to the Veteran's electronic healthcare information. We propose to address scientific gaps by focusing on multiple ethnicities, rare variants, and antecedent risk factor levels using the MVP cohort. In the proposed study, we first create a virtual baseline exam by developing methods to link data from MVP baseline examination to the VA electronic health record using a systematic approach. Results for Veterans are influenced by geographic region in the U.S., race/ethnicity, frequency of outpatient clinic visits, and other variables. Based on our systematic approach of handling MVP questionnaire data and the electronic healthcare data, we assess the genome-wide associations of both common and rare alleles with CVD RFs in causal pathways, with consideration of the environment (diet quality, pharmacological treatment), and assessment of current and antecedent RF levels. Methods include single VA outpatient measurements of quantitative CVD RFs (LDL-C, non- HDL-C, triglycerides, body mass index) with and without diet quality adjustment using the Willett Food Frequency Questionnaire performed at the MVP baseline visit. Other methods include pharmacologic treatment of CVD RFs to derive imputed untreated RF levels, and antecedent quantitative CVD RFs measured at VA outpatient visits 5 and 10 years before the MVP baseline visit when such data are available. We will perform common variant association studies (CVAS) and rare variant association studies (RVAS) testing the association of genetic variants to quantitative CVD risk for a) prevalent coronary heart disease (CHD) [myocardial infarction, history of coronary bypass grafting (CABG), history of percutaneous coronary intervention (PCI)] and b) prevalent atherothrombotic stroke, with comparison of effects by race and ethnicity, and c) examine the multigenic association of CHD and stroke using the genetic risk score (GRS) of validated CVD-associated SNPs within and across ethnicity. This project will provide a platform for CVD incidence analyses for MVP participants across the VA in the future. Furthermore, the proposed study findings will allow for the comparison of the impact of genetic variants on cardio metabolic RFs risk factors and atherosclerotic disease prevalence across AA, HA, and EA Veterans. CVD accounts for an extremely large health care burden in veterans. This project will investigate the role of genetic and environmental determinants of CVD risk factors in MVP participants across different ethnic and racial groups.