The H3Africa Kidney Disease Cohort Study

 描述(由申请人提供)：由于慢性肾脏疾病(CKD)和肾小球肾炎(GN)的发病率较高，非洲裔美国人(AA)患终末期肾脏疾病(ESRD)的终身风险比非西班牙裔白人(7.8%至2.8%)高三倍以上。最近的研究表明，生活在撒哈拉以南非洲(SSA)的黑人(非洲黑人)可能与再生障碍性贫血一样有患肾脏疾病的高倾向性，这两个群体(美国黑人和非洲黑人)的相似之处可能是肾脏疾病的共同遗传易感性；其中最值得注意的是编码载脂蛋白L1的APOL1肾脏风险变异体。循环载脂蛋白L1作为一种能杀死人血清中锥虫寄生虫的锥虫溶解因子，可能对36个非洲国家流行的锥虫病(“非洲昏睡病”)具有保护作用。据估计，300多万再生障碍性贫血和5000多万非洲黑人由于临床定义的肾病(高血压、糖尿病、镰刀病等)而患有慢性肾脏病。和GN。其中很大一部分将进展为终末期肾病，这是非洲地区由于缺乏透析或肾移植而即将死亡的先兆。以我们在AA(Parsa A.N Eng J Med 2013；369(23)：2183-960&Lipkowitz女士Kidney Int 2013；83(1)：114-20)以及非洲黑人(Science 2014；344(6190)：1346-9&Tayo BO)的工作为基础。InUrol Nephrol 2013；45(2)485-94)，我们在此建议利用正在进行的、由NIH资助的病例对照H3非洲肾脏疾病研究中的资源和专业知识，在3000名患有临床定义的肾脏疾病的参与者和1000名患有活检证实的事件肾小球疾病的参与者中进行一项跨国前瞻性队列研究，以完成以下研究目标：(1)确定APOL1风险变量是否独立预测非洲黑人肾脏疾病的进展，并确定非洲黑人肾脏疾病进展的可改变的危险因素；(2)按国家(n=4)和区域(东非和西非)阐明基因-环境相互作用(APOL1-感染)的起因作用及其对非洲黑人GN结果的联合和几个影响；(3)为肾脏疾病和其他慢性疾病的基础、临床和翻译研究建立高质量的资源(血液、尿液、DNA、RNA和肾脏组织的数据和标本库)。这项拟议的研究具有创新性，因为它是第一个充分有效的前瞻性队列研究，既确定了SSA肾病进展的遗传决定因素，又描述了其表型。这项研究的总体影响可能非常大，因为它将：(I)产生与开发肾脏疾病筛查计划、预防策略和治疗干预试验相关的新信息，以及(Ii)为所有非洲血统的人的肾脏疾病的基础、临床和翻译研究创建一个新的平台Essentia。换句话说，这一独特的研究资源将使世界各地的研究人员很容易获得。

 DESCRIPTION (provided by applicant): African Americans (AA) have a greater than three-fold higher lifetime risk of end stage renal disease (ESRD) as compared to non-Hispanic Whites (7.8% to 2.8%) secondary to a higher prevalence of both chronic kidney disease (CKD) and glomerulonephritides (GN). Recent studies suggest that Blacks living in Sub-Saharan Africa (SSA) (African Blacks) may have a similarly high predilection to kidney disease as do AA and that underlying this similarity in the two populations (American and African Blacks) may be common genetic predispositions to kidney disease; the most notable of which are the APOL1 kidney risk variants that encode for apolipoprotein L1. Circulating apolipoprotein L1 acts as a trypanolytic factor capable of killing trypanosome parasites in human serum and may be protective against trypanosomiasis ("African sleeping sickness") which is endemic in 36 African countries. It is estimated that more than three million AA and greater than 50 million African Blacks have CKD due to clinically defined nephropathies (from hypertension, diabetes mellitus, sickle disease, etc.) and GN. A significant fraction of these will progress to ESRD which is a harbinger of imminent death in the African setting due to the scarcity of dialysis or kidney transplantation. Building on our work in AA (Parsa A. N Eng J Med 2013;369(23):2183-960 & Lipkowitz MS. Kidney Int 2013;83(1):114-20) as well as in African Blacks (Science 2014;344(6190):1346-9 & Tayo BO. Int Urol Nephrol 2013;45(2)485-94), we herein propose to leverage the resources and expertise in the ongoing, NIH-funded, case-controlled H3Africa Kidney Disease Study to conduct a multinational prospective cohort study in 3,000 participants with clinically defined nephropathies and in 1,000 participants with biopsy-confirmed incident glomerular disease (for a total sample size of 4,000 HIV-negative African Blacks with kidney disease) to accomplish the following research objectives: (1) determine whether APOL1 risk variants independently predict kidney disease progression and identify modifiable risk factors for kidney disease progression in African Blacks; (2) elucidate the causative role of gene-environment interactions (APOL1-infections) and their joint and several effects on the outcomes of GN among African Blacks by country (n=4) and region (East vs. West Africa) and (3) establish a high quality resource (data and specimen repository of blood, urine, DNA, RNA and kidney tissue) for basic, clinical and translational research in kidney disease and other chronic diseases. The proposed study is innovative in that it is the first adequately powered prospective cohort study to both identify the genetic determinants and characterize the phenotype for kidney disease progression in SSA. The overall impact of the study is likely to be very high as it would: (i) yield new information relevant for the development of kidney disease screening programs, preventative strategies and therapeutic intervention trials and (ii) create a new platform essentia for basic, clinical and translational studies of kidney disease in all people of African ancestry. o wit, this unique research resource would be made readily accessible to researchers worldwide.