Genetic underpinnings of cardiorenal risk in Africans and African Americans

摘要 高血压 (HTN) 在非裔美国人 (AA) 中发病较早，且形式更为严重，如下所示： 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。相关合并症（包括 2 型）的发生率 糖尿病 (T2D) 和慢性肾病 (CKD) 的 AA 含量也较高。这些显着的差异等同于 对 AA 社区的健康产生重要影响。新数据表明遗传标记 原产于非洲的病毒会给该人群带来疾病风险。先前对 HTN、T2D 和 CKD 已在 AA 中进行。然而，祖先遗传变异的覆盖范围和样本量 欧洲血统人群的遗传研究已取得成果，但尚未取得成果 非洲血统人群。此外，直接比较 AA 和非洲人之间的风险等位基因 人口尚未形成。为了解决这些重要的研究空白，我们提出了一项研究 大大扩展了具有相关表型和基因型数据的 AA 数量，并且显着 提高了属于现有的大量 AA 中非洲特定遗传变异的覆盖范围 心血管流行病学队列。我们建议对来自地理和地理原因的 8000 个 AA 进行基因分型 中风的种族差异 (REGARDS) 研究和 2000 名西非人的人类健康和遗传 非洲 (H3A) 肾脏网络，新将这 10,000 名参与者纳入基因研究。我们将结合 这些数据与来自 2000 名 H3A 参与者的现有基因型数据以及最近生成的高覆盖率 来自 NHLBI Trans- 的约 6500 个 AA 的全基因组序列 (WGS) 数据以及相关表型数据 精准医学组学 (TOPMed) 计划。 TOPMed WGS 数据将进一步用于估算 REGARDS、H3A 和约 15,000 名之前来自其他国家的基因分型 AA 参与者的序列变体 NHLBI 队列。我们将利用这些前所未有的资源来进行最全面的研究 迄今为止 AA 中的心肾特征（血压、肾功能、空腹血糖）。我们会跟进我们的顶 11,000 个 AA 的独立复制样本中的变异关联结果及相关数据。最后，我们 将测试与这些危险因素相关的变异是否也与 CVD 结果相关。我们的 拟议的研究总共包括约 40,500 名 AA 和 4000 名西非人，将为我们提供前所未有的研究 有机会评估遗传变异，特别是源自非洲的遗传变异，在 AA 人群对 CVD 和肾脏疾病的易感性增加。 ！

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. !