Renal Disease Progression in African Americans

描述(申请人提供)：糖尿病肾病是世界上慢性肾脏疾病的主要原因。尽管已经确定了一些可改变的危险因素，但来自高加索人和皮马印第安人的数据表明，糖尿病肾病是由基因决定的。维克森林大学(WFU)的研究小组已经证明，与白人相比，非裔美国人(AA)患糖尿病肾病的风险更大。为了确定糖尿病肾病的易感基因，凯斯西储大学(Case Western Reserve University，CWRU)和WFU小组正在进行NIH资助的项目，并参与NIH赞助的肾病和糖尿病家庭调查(FIND)联盟。与这些根据离散表型对受试者进行分类的研究不同，复杂疾病的遗传基础可能更容易通过替代策略来完成，其中包括将表型解构为连续的数量性状。在我们现有研究的基础上，我们假设中间表型、蛋白尿和肾小球滤过率(GFR)的变化分别预测和衡量糖尿病肾病向终末期肾病的进展是可遗传的。这一假说将在对再生障碍性贫血和高加索家族的纵向研究中得到验证，这将首次确定再生障碍性贫血中糖尿病肾病的自然历史。数据将由数量性状基因座(QTL)分析产生，这为正在进行的策略提供了优势，包括登记和更好地定义具有中间表型(例如微量白蛋白尿)的糖尿病肾病受试者的临床病程，这些表型以前在我们正在进行的基因分析中被排除在外。我们的具体目标是(1)将通过已经登记在FIND研究中的患有ESRD继发于糖尿病肾病的索引病例来确定AA和高加索家庭。他们的糖尿病同胞(n=1200，约60%AA)将进行表型分析和纵向随访。相关结果将包括每年的尿白蛋白排泄量和GFR测量；(2)为了评估基因组区域与蛋白尿和GFR变化的中间、定量表型的关联，将使用分子和统计方法来检查已通过Find基因组扫描确定的与糖尿病肾病相关的区域。病例和对照将使用单变量和多变量方法进行比较。环境相关因素将包括在模型中。

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.