Genetics of Renal Disease in African Americans

局灶性节段性肾小球硬化(FSGS)是一种特发性肾小球硬化，与HIV感染相关，两者在非裔美国人(AA)中更为常见。FSGS的发病机制尚不清楚，目前还没有有效的治疗方法。我们假设，非洲人后裔中存在的一个或多个基因，在暴露于特定的环境因素(如艾滋病毒感染)后，容易患上FSGS。在NIDDK肾脏病科的合作下，已经启动了一项多中心研究，涉及13个壁外站点。我们已经积累了200名患有FSGS的AA患者和210名静脉注射吸毒者，他们感染艾滋病毒至少8年，但仍保持正常的肾功能。我们正在使用候选基因方法来识别与FSGS表型相关的标记。在初步分析中，已对258例患者和对照组的22个双等位候选基因进行了基因分型。本研究发现转化生长因子β1(TGFb1)基因启动子和第一外显子的两个多态位点与FSGS表型相关。对转化生长因子(TGFb1)等位基因的分析提供了证据，表明野生型(祖先)单倍型可能通过上调转化生长因子β1蛋白而增加患FSGS的风险。血管紧张素转换酶基因ACEALU插入/缺失突变也与FSGS相关(p=0.001)。由于ACE基因中有70多个已识别的SNPs，因此不可能辨别该突变本身是否影响疾病的致病途径，或者该插入是否与尚未检测到的易感基因连锁不平衡。我们目前正在使用单倍型分析和序列分析来解决这种不确定性。

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 such as HIV infection. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 200 AA 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 this study to be associated with the FSGS phenotype. Analysis of the TGF(TGFb1) alleles provides evidence that the wildtype (ancestral) haplotype is associated with increased risk of FSGS, possibly by the up-regulation of TGF beta 1 protein. The alu insertion/deletion mutation in the angiotensin converting enzyme gene ACE is also associated with FSGS (p=0.001). As there are more than 70 identified SNPs in the ACE gene, it is not possible to discern if this mutation is itself affecting the causal pathway of the disease or if the insertion is in linkage disequilibrium with an as yet undetected susceptibility locus. We are currently using haplotype analysis and sequence analysis to resolve this uncertainty.