Genetics of Renal Disease in African Americans

局灶节段性肾小球硬化症（FSGS）以特发性形式发生，并与HIV感染相关，这两种疾病在非洲裔美国人（AA）中更常见。FSGS的发病机制仍然是一个未知数，并没有有效的治疗已被证明。我们假设，一个或多个基因，存在于非洲人后裔，易患FSGS暴露于特定的环境因素，在这种情况下，艾滋病毒感染。与NIDDK肾脏病科合作，启动了一项有13个院外研究中心的多中心研究。我们已累计222 AA和89欧洲美国人（EA）与FSGS和210静脉注射吸毒者已感染艾滋病毒至少八年，但保留正常的肾功能。我们正在使用候选基因的方法来确定与FSGS表型相关的标记。在初步分析中，258例病例和对照已被分型为22个双等位基因候选基因。转化生长因子β 1（TGFB 1）基因启动子和第一外显子中的两个多态性位点已通过单倍型分析显示与FSGS表型相关。对TGFB 1等位基因的分析已经确定，祖先单倍型与FSGS风险增加相关，可能是通过TGF β 1蛋白的上调。我们通过测量已知TGFB 1基因型的志愿捐献者的血浆TGF β 1蛋白水平来验证这一假设。 血管紧张素转换酶基因ACE中的alu插入/缺失（ins/del）突变也与AA中的FSGS相关（p=0.001）。由于在ACE基因中有超过70个已鉴定的单核苷酸多态性（SNP），因此不可能辨别插入/缺失本身是否影响疾病的因果途径或通过连锁不平衡追踪因果位点。我们已经完成了FSGS病例和对照的ACE基因测序，以确定单倍型结构，确定与插入/缺失连锁不平衡的SNP，并确定致病单倍型等位基因。这项研究也将提供深入了解ACE等位基因在高血压中的作用，高血压是影响AA的重要心血管危险因素。

Focal segmental glomerulosclerosis (FSGS) occurs in an idiopathic form and in association with HIV infection, both of which are more common among African Americans (AA). The pathogenesis of FSGS remains an unknown and no effective therapy has been demonstrated. We hypothesize that a gene or genes, present in people of African descent, predisposes to FSGS following exposure to particular environmental factors, in this case, HIV infection. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 222 AA and 89 European Americans (EA) with FSGS and 210 intravenous drug users who have been infected with HIV for at least eight years but retain normal kidney function. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, 258 cases and controls have been genotyped for 22 diallelic candidate genes. Two polymorphic sites in the promoter and first exon of the transforming growth factor beta 1(TGFB1) gene have been shown by haplotype analysis to be associated with the FSGS phenotype. Analysis of the TGFB1 alleles has determined that the ancestral haplotype is associated with increased risk of FSGS, possibly by the up-regulation of TGF beta 1 protein. We are testing this hypothesis by measuring plasma TGF beta 1 protein levels in volunteer donors of known TGFB1 genotypes. The alu insertion/deletion (ins/del) mutation in the angiotensin converting enzyme gene ACE is also associated with FSGS (p=0.001) in AA. As there are more than 70 identified single nucleotide polymorphisms (SNPs) in the ACE gene, it is not possible to discern if the ins/del is itself affecting the causal pathway of the disease or is tracking through linkage disequilibrium the causal site. We have completed sequencing the ACE gene in FSGS cases and controls to determine haplotype structure, identify SNPs in linkage disequilibrium with the ins/del, and identify the causative haplotype alleles. This study should also provide insight into the role of ACE alleles in hypertension, an important cardiovascular risk factor disproportionality affecting AA.