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. .

抽象的 高血压（HTN）和慢性肾脏疾病（CKD）过度的非洲裔美国人（AAS）。这些差异 转化为较高的心脏疾病终点，包括中风，冠心病（CHD），结束 阶段肾脏疾病（ESRD）和死亡。血压（BP）降低降压治疗可降低 这些结果的风险，但是在不同种族组中，治疗的影响可能会发生变化。研究有 证明AA对钙通道阻滞剂和利尿剂的反应最佳，而对β- 与其相比 欧美（EA）对应。心脏健康和降压性差异的原因 治疗反应是多因素的，被认为包括环境和遗传因素。事先的 HTN和BP对降压药反应的遗传和药物遗传学关联研究具有 是在AAS中进行的，但是这些研究的范围和样本量相比已小心。 给EA人群的人。现有遗传数据集的较小样品大小会阻碍多基因风险 该人群的预测有可能创建新的健康分布。为了克服限制 在先前的研究并实现AAS中的个性化医学方面，我们将利用现有的数据 迄今为止，心脏特征最大的基因组和药物基因组学研究之一。我们的 药物遗传学发现包括> 4000 AA随机分配给氯噻酮，> 2500随机分配给 Genhat研究的Lisinopril，这是一项抗高血压和脂质降低处理的辅助研究 防止心脏病发作试验。我们已经与国际财团建立了协议 抗高素质药物基因组学研究（ICAP）用于验证我们的发现。我们的基因组发现是 锚定在全基因组估算的GWAS数据中，来自〜12000个问候AA参与者和〜5000 AA （JHS，热那亚，超基因）具有来自NHLBI的跨词的相关表型和基因型数据 精密医学（顶部）计划。我们将在其他方面复制我们的顶级变体关联结果 人口（约11,000 AA），具有相关数据，然后在其他同类中进行多基因风险评分测试 顶。使用这些丰富的资源，我们将得出新的筛查工具，以进行降压治疗反应 和心脏疾病。多基因风险评分应用在其他人群中正在增加，这项研究 将在代表性不足的AA中大大改善可用数据。