Genetic underpinnings of cardiorenal risk in Africans and African Americans

摘要 高血压(HTN)在非裔美国人(AAS)中起病更早，并呈现更严重的形式，因为 与其他美国人口相比，这意味着心血管疾病(CVD)的发病率更高 终点包括中风和终末期肾病。包括2型在内的相关合并症的发生率 糖尿病(T2D)和慢性肾脏疾病(CKD)在AAS中也较高。这些显著的差异等同于 对AA社区的健康产生重要影响。新出现的数据表明遗传标记 起源于非洲的病毒会在该人群中引发疾病风险。HTN、T2D和HtN的遗传关联研究 CKD已在AAS进行。然而，祖先的遗传变异覆盖率和样本量 已经在欧洲祖先群体的遗传学研究中取得了进展，但还没有达到 非洲血统的人口。此外，AA和非洲人之间的风险等位基因的直接比较 种群数量尚未确定。为了解决这些重要的研究差距，我们提出了一项研究， 使用相关的表型和基因数据大幅扩展AA的数量，并显著 提高了非洲特有的遗传变异在现有的大量AA中的覆盖率 心血管流行病学队列。我们建议对8000个氨基酸进行基因分型，从地理和 中风的种族差异研究和2000名西非人的人类健康和遗传 在非洲(H3A)肾脏网络，新将这10,000名参与者纳入基因研究。我们将联合起来 这些数据与2000名H3A参与者的现有基因数据和最近产生的高覆盖率 ~6500个氨基酸的全基因组序列(WGS)数据，以及相关的表型数据，来自NHLBI的TRANS- 精准医学组学(TOPMed)计划。TOPMed WGS数据将进一步用于估算 H3A和来自其他地区的约15,000名先前分型的AA参与者的序列变异 NHLBI队列。我们将利用这些史无前例的资源，对 迄今AAS患者的心肾特征(血压、肾功能、空腹血糖)。我们将跟进我们的最高 在包含相关数据的11,000个AA的独立复制样本中发现了变异关联。最后，我们 将测试与这些风险因素相关的变异是否也与心血管疾病的结果相关。我们的 拟议的研究，包括总共40,500名AA和4,000名西非人，将为我们提供前所未有的 有机会评价遗传变异，特别是非洲衍生的遗传变异在 AAS患者对心血管疾病和肾脏疾病的易感性增加。 好了！

ABSTRACT Hypertension (HTN) has earlier onset and takes on a more severe form in African Americans (AAs) as compared to other U.S. populations, which translates to higher rates of cardiovascular disease (CVD) endpoints including stroke and end stage renal disease. The rates of related comorbidities including type 2 diabetes (T2D) and chronic kidney disease (CKD) are also higher in AAs. These remarkable disparities equate to important consequences for the health of AA communities. Emerging data suggest genetic markers originating in Africa incur disease risk in this population. Prior genetic association studies of HTN, T2D, and CKD have been undertaken in AAs. However, the ancestral genetic variation coverage and sample sizes that have been achieved in genetic studies of European Ancestry populations have not yet been achieved for African ancestry populations. Additionally, a direct comparison of risk alleles between AA and African populations has yet to be made. To address these important research gaps, we propose a study that substantially expands the number of AAs with relevant phenotype and genotype data and dramatically improves the coverage of African specific genetic variation in a large number of AAs belonging to existing cardiovascular epidemiology cohorts. We propose genotyping 8000 AAs from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study and 2000 West Africans from the Human Health and Heredity in Africa (H3A) Kidney Network, newly bringing these 10,000 participants into genetic studies. We will combine these data with existing genotype data from 2000 H3A participants and recently generated high-coverage whole genome sequence (WGS) data on ~6500 AAs, with relevant phenotype data, from the NHLBI’s Trans- Omics for Precision Medicine (TOPMed) program. The TOPMed WGS data will be further used to impute sequence variants into REGARDS, H3A and the ~15,000 previously genotyped AA participants from other NHLBI cohorts. We will use these unprecedented resources to conduct the most comprehensive study of cardiorenal traits (blood pressure, renal function, fasting glucose) in AAs to date. We will follow up our top variant-association findings in an independent replication sample of 11,000 AAs with relevant data. Finally, we will test whether variants associated with these risk factors are also associated with CVD outcomes. Our proposed study, including a total of ~40,500 AAs and 4000 West Africans, will provide us an unprecedented opportunity to evaluate the role of genetic variation, and in particular African-derived genetic variation, in the increased susceptibility to CVD and renal disease in AAs. !