Renal Disease Progression in African Americans

描述（由申请人提供）：糖尿病肾病（DN）是世界上慢性肾脏疾病的主要原因。虽然已经确定了一些可改变的风险因素，但来自高加索人和皮马印第安人的数据表明DN是由遗传决定的。维克森林大学（WFU）的研究小组已经证明，与白人相比，非洲裔美国人（AA）患糖尿病肾病的风险更大。为了确定DN易感基因座，凯斯西储大学（CWRU）和WFU小组正在进行NIH资助的项目，并参加NIH赞助的肾病和糖尿病家庭调查（FIND）联盟。与这些研究不同，这些研究通过离散的表型对受试者进行分类，通过替代策略（包括将表型解构为连续的数量性状），可以更容易地解开复杂疾病的遗传基础。基于我们现有的研究，我们假设中间表型、蛋白尿和肾小球滤过率（GFR）的变化是可遗传的，它们分别预测和测量糖尿病肾病向ESRD的进展。这一假设将在AA和白人家庭的纵向研究中进行检验，这将首次定义AA中DN的自然史。将通过数量性状基因座（QTL）分析生成数据，这为正在进行的策略提供了优势，包括招募和更好地定义具有中间表型（例如微量白蛋白尿）的DN受试者的临床病程，这些表型先前已被排除在我们正在进行的遗传分析之外。我们的具体目标是（1）通过FIND研究中已入组的继发于DN的ESRD索引病例确定AA和白人家族。他们的糖尿病同胞（n = 1200，约60% AA）将表型和纵向跟踪。依赖性结局将包括每年尿白蛋白排泄和GFR测量，（2）为了评估基因组区域与蛋白尿和GFR变化的中间定量表型的相关性，将使用分子和统计学方法来检查提示与DN相关的区域，这些区域已通过FIND基因组扫描鉴定。将使用单变量和多变量方法比较病例和对照。模型中将包括环境相关因素。

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the leading cause of chronic renal disease in the world. Though some modifiable risk factors have been identified, data from Caucasians and Pima Indians indicate that DN is genetically determined. The Wake Forest University (WFU) group has demonstrated that African Americans (AA) are at greater risk for DN compared to Caucasians. To identify DN susceptibility loci, the Case Western Reserve University (CWRU) and WFU groups are conducting NIH-funded projects and participating in the NIH-sponsored Family Investigation of Nephropathy and Diabetes (FIND) consortium. In contrast to these studies, which categorize subjects by discrete phenotypes, unraveling the genetic basis of complex diseases may be more easily accomplished through alternative strategies that include deconstructing phenotypes into continuous, quantitative traits. Building on our existing studies, we hypothesize hat the intermediate phenotypes, proteinuria and glomerular filtration rate (GFR) change, which respectively predict and measure progression of diabetic nephropathy to ESRD, are heritable. The hypothesis will be tested in a longitudinal study of AA and Caucasian families, which will permit the natural history of DN in AA to be defined for the first time. Data will be generated by quantitative trait locus (QTL) analysis, which offers advantages to the ongoing strategies, including enrollment and better definition of the clinical course of DN subjects with intermediate phenotypes (e.g. microalbuminuria), which have previously been excluded in our ongoing genetic analyses. Our specific aims are (1) AA and Caucasian families will be ascertained through index cases already enrolled in the FIND study with ESRD secondary to DN. Their diabetic siblings (n = 1200, about 60% AA) will be phenotyped and followed longitudinally. Dependent outcomes will include yearly urine albumin excretion and GFR measurements, (2) to assess association of genomic regions with the intermediate, quantitative phenotypes of proteinuria and GFR change, molecular and statistical methods will be used to examine regions suggestive of linkage with DN, which have been identified by the FIND genome scan. Cases and controls will be compared using both univariate and multivariate approaches. Environmental correlates will be included in the models.