Cardiorenal Genomics for Risk Prediction in African Descent Populations

摘要 高血压(HTN)和慢性肾脏疾病(CKD)使非裔美国人(AAs)负担过重。这些差距 转化为更高的心肾疾病终点比率，包括中风、冠心病(CHD)，完 肾脏疾病(ESRD)阶段，以及死亡。降压治疗可降低血压 这些结果的风险，但治疗的效果可能在不同的种族群体中有所不同。研究表明， 研究表明，AAs对钙通道阻滞剂和利尿剂的反应最好，而对β-氨基丁酸的反应不是很好。 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其 欧美(EA)同行。心肾健康与抗高血压差异的原因 治疗反应是多因素的，被认为既包括环境因素，也包括遗传因素。之前 HTN和BP对抗高血压药物的反应的遗传学和药物遗传学关联研究 这些研究是在美国儿科学会进行的，但与之相比，这些研究的范围和样本量要小得多 对EA种群的影响。现有遗传数据集的较小样本量阻碍了多基因风险 对这一人群的预测有可能造成新的健康差距。为了克服这些限制， 并使AAS在个性化医疗方面的努力成为可能，我们将利用现有的数据 这是迄今为止规模最大的心肾特征基因组和药物基因组研究之一。我们的 药物遗传学的发现包括将&gt；4000个AA随机分配给氯替利酮，将&gt；2500随机分配到 赖诺普利来自GenHAT研究，这是一项关于降压和降脂治疗的辅助研究 预防心脏病发作试验。我们已经与国际财团达成了一项协议 抗高血压药物药物基因组学研究(ICAPS)以验证我们的发现。我们的基因组发现是 植根于来自~12000名AA研究参与者和~5,000名AA的全基因组数据 (JHS，Genoa，HyperGEN)，以及来自NHLBI的Trans-Omics for 精准医学(TOPMed)计划。我们将在另一篇文章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个AA)，随后在来自以下地点的其他队列中进行多基因风险得分测试 TOPMed。利用这些丰富的资源，我们将开发出新的抗高血压治疗反应筛查工具 以及心脏和肾脏疾病。多基因风险评分在其他人群中的应用正在增加，这项研究 将极大地改善代表性不足的区域的现有数据。。

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. .