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）和慢性肾病（CKD）给非裔美国人（AA）带来了沉重的负担。 转化为更高的心肾疾病终点发生率，包括中风、冠心病 (CHD)、 阶段性肾病 (ESRD) 和抗高血压治疗降低的血压 (BP) 会减少。 这些结果的风险，但治疗效果在不同种族群体中可能有所不同。 AA 对钙通道阻滞剂和利尿剂的反应最好，而对 β- 阻滞剂、血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂与它们的比较 欧洲裔美国人 (EA) 盟友在心肾健康和抗高血压方面存在差异的原因。 治疗反应是多因素的，被认为包括环境因素和遗传因素。 HTN 和 BP 对抗高血压药物反应的遗传和药物遗传学关联研究 AA 中进行了这些研究，但与其他研究相比，这些研究的范围和样本量要小得多 现有遗传数据集的较小样本量阻碍了多基因风险。 预测这一人群有可能造成新的健康差异，以克服这些限制。 之前的研究并促进 AA 中个性化医疗的努力，我们将利用现有的数据 迄今为止最大的心脏肾脏特征基因组和药物基因组研究之一的队列。 药物遗传学发现包括 >4000 个随机分配到氯噻酮的 AA 和 >2500 个随机分配到氯噻酮的 AA 赖诺普利来自 GenHAT 研究，这是一项抗高血压和降脂治疗的辅助研究 我们已与国际联盟达成了预防心脏病试验的协议。 抗高血压药物基因组学研究（ICAPS）验证了我们的基因组发现。 锚定于约 12000 名 REGARDS 研究 AA 参与者和约 5000 名 AA 的全基因组估算 GWAS 数据 （JHS、热那亚、HyperGEN）以及来自 NHLBI 跨组学的相关表型和基因型数据 我们将在其他项目中复制我们的顶级变异关联研究结果。 人群（约 11,000 个 AA）以及相关数据，然后在其他队列中进行多基因风险评分测试 TOPMed。利用这些丰富的资源，我们将获得抗高血压治疗反应的新筛查工具。 多基因风险评分在其他人群中的应用正在增加，这项研究也正在增加。 将大大改善代表性不足的 AA 中的可用数据。