Cardiorenal Genomics for Risk Prediction in African Descent Populations

用于非洲裔人群风险预测的心肾基因组学

• 批准号: 10677548
• 负责人: Marguerite R Irvin
• 金额: $ 86.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677548
• 关键词: Adrenergic beta-Antagonists; African American population; African ancestry; Agreement; American; Ancillary Study; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiorenal syndrome; Cessation of life; Chlorthalidone; Chronic Kidney Failure; Clinic; Coronary heart disease; Data; Data Set; Disease; Disparity; Diuretics; End stage renal failure; Environmental Risk Factor; European; Genetic; Genetic Markers; Genomics; Genotype; Health; Hypertension; International; Kidney Diseases; Lipids; Lisinopril; Measures; Myocardial Infarction; National Heart, Lung, and Blood Institute; Outcome; Participant; Pharmacogenetics; Pharmacogenomics; Phenotype; Population; Prevention; Randomized; Research; Resources; Risk Reduction; Sample Size; Screening procedure; Stroke; Testing; Trans-Omics for Precision Medicine; Translating; Variant; Work; cohort; genetic risk factor; genome wide association study; health disparity; improved; novel; personalized medicine; polygenic risk score; prevent; programs; racial population; response; risk prediction; trait; treatment effect; treatment response; validation studies; whole genome

ABSTRACT Hypertension (HTN) and chronic kidney disease (CKD) overburden African Americans (AAs). These disparities translate to higher rates of cardiorenal disease endpoints including stroke, coronary heart disease (CHD), end stage renal disease (ESRD), and death. Blood pressure (BP) lowering with antihypertensive treatment reduces the risk of these outcomes, but the effects of treatment may be variable in different race groups. Studies have demonstrated that AAs respond best to calcium channel blockers and diuretics and not as well to to beta- blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers in comparison to their European American (EA) counterparts. The reasons for differences in cardiorenal health and antihypertensive treatment response are multifactorial and thought to include both environmental and inherited factors. Prior genetic and pharmacogenetic association studies of HTN and BP response to antihypertensive agents have been undertaken in AAs, but these studies have been considerably smaller in scope and sample size compared to those of EA populations. Smaller samples sizes of existing genetic datasets have hindered polygenic risk prediction in this population with the potential to create new health disparities. In order to overcome the limitations of previous research and enable efforts in personalized medicine in AAs, we will leverage data from existing cohorts for one of the largest genomic and pharmacogenomic studies of cardiorenal traits to date. Our pharmacogenetic discovery includes >4000 AAs randomized to chlorthalidone and >2500 randomized to lisinopril from the GenHAT study, an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. We have established an agreement with the International Consortium for Antihypertensives Pharmacogenomics Studies (ICAPS) for validation of our findings. Our genomic discovery is anchored in whole-genome imputed GWAS data from ~12000 REGARDS study AA participants and ~5000 AAs (JHS, Genoa, HyperGEN) with relevant phenotype and genotype data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. We will replicate our top variant-association findings in additional populations (~11,000 AAs) with relevant data followed by polygenic risk score testing in other cohorts from TOPMed. Using these rich resources we will derive new screening tools for antihypertensive treatment response and cardiorenal diseases. Polygenic risk score applications are increasing in other populations and this research will substantially improve the available data in underrepresented AAs. .

摘要 高血压（HTN）和慢性肾脏疾病（CKD）使非洲裔美国人（AAs）负担过重。这些差距 转化为心肾疾病终点的发生率更高，包括卒中、冠心病（CHD）、终末期肾病（CHD）、 阶段性肾病（ESRD）和死亡。降压治疗降低血压（BP） 这些结果的风险，但治疗的效果在不同的种族群体中可能是可变的。研究 表明AA对钙通道阻滞剂和利尿剂的反应最好，而对β- 阻断剂、血管紧张素转化酶抑制剂或血管紧张素受体阻断剂，与它们的 欧洲美洲（EA）同行。心肾健康和抗高血压药物差异的原因 治疗反应是多因素的，被认为包括环境和遗传因素。之前 HTN和BP对降压药反应的遗传学和药物遗传学关联研究， 在AA中进行，但这些研究在范围和样本量上都要小得多， 与EA人口的比例。现有遗传数据集的较小样本量阻碍了多基因风险 这一预测可能会造成新的健康差距。为了克服局限性 以前的研究，并使个性化医疗的努力在AA，我们将利用现有的数据， 这是迄今为止最大的心肾性状基因组学和药物基因组学研究之一。我们 药物遗传学发现包括>4000例随机分配至氯噻酮的AA和>2500例随机分配至 GenHAT研究中的赖诺普利，这是一项抗高血压和降脂治疗的辅助研究， 预防心脏病发作试验。我们已与国际财团达成协议， 抗高血压药物基因组学研究（ICAPS）验证我们的研究结果。我们的基因组发现 锚定在来自约12000例REGARDS研究AA参与者和约5000例AA参与者的全基因组插补GWAS数据中 (JHS，Genoa，HyperGEN）与来自NHLBI的Trans-Omics的相关表型和基因型数据， 精准医学（TOPMed）计划。我们将在其他研究中复制我们的顶级变异关联发现， 具有相关数据的人群（约11，000例AA），然后在其他队列中进行多基因风险评分检测， 顶。利用这些丰富的资源，我们将获得新的筛选工具，抗高血压治疗反应 和心肾疾病。多基因风险评分在其他人群中的应用越来越多，这项研究 将大大改善代表性不足的AA的可用数据。.