Genetic underpinnings of cardiorenal risk in Africans and African Americans

摘要 高血压（HTN）在非洲裔美国人（AAs）中发病较早， 与其他美国人群相比，这意味着心血管疾病（CVD）的发病率更高 终点包括卒中和终末期肾病。相关合并症的发生率，包括2型 糖尿病（T2 D）和慢性肾病（CKD）在AA中也较高。这些显著的差异 对AA社区的健康产生重要影响。新数据表明遗传标记 原产于非洲的人在这一人群中产生疾病风险。HTN、T2 D和T2 D的既往遗传关联研究 CKD已在AA中进行。然而，祖先遗传变异的覆盖率和样本量， 在欧洲野生动物种群的遗传研究中已经取得了进展，但尚未取得进展。 非洲血统的人口。此外，直接比较AA和非洲之间的风险等位基因， 人口还没有形成。为了解决这些重要的研究空白，我们提出了一项研究， 大大增加了具有相关表型和基因型数据的AA的数量， 提高了非洲特定的遗传变异的覆盖面，在大量的AA属于现有的 心血管流行病学队列。我们建议对8000个AA进行基因分型， 中风的种族差异（REGARDS）研究和来自人类健康和遗传的2000名西非人 在非洲（H3 A）肾脏网络，最近将这10,000名参与者纳入遗传研究。我们将联合收割机 这些数据与来自2000名H3 A参与者的现有基因型数据相结合，最近产生了高覆盖率， 全基因组序列（WGS）数据约6500 AA，相关表型数据，从NHLBI的跨- Omics for Precision Medicine（TOPMed）TOPM化WGS数据将进一步用于插补 序列变异进入REGARDS，H3 A和约15，000名先前基因分型的AA参与者， NHLBI队列。我们将利用这些前所未有的资源， 迄今为止，AA的心肾特征（血压、肾功能、空腹血糖）。我们将跟进我们的顶部 包含11，000个AA的独立复制样本中的变异关联发现及相关数据。最后我们 将测试与这些风险因素相关的变异是否也与CVD结果相关。我们 一项拟议的研究，包括总共约40,500名AA和4000名西非人，将为我们提供前所未有的 有机会评估遗传变异的作用，特别是非洲衍生的遗传变异， AA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. !