Genetics of Renal Disease in African Americans

局灶性节段性肾小球硬化(FSGS)以特发性形式发生，并与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，存在于非洲人后裔中的一个或多个基因，在暴露于特定的环境因素后，容易患上FSGS，在这种情况下，就是艾滋病毒感染。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222名患有FSGS的AA和89名欧洲美国人(EA)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。单倍型分析表明，转化生长因子β1基因启动子和第一外显子上的两个多态位点与FSGS表型相关。对TGFB1等位基因的分析已经确定，祖先的单倍型与FSGS风险的增加有关，可能是通过上调转化生长因子β1蛋白。我们正在通过测量已知TGFB1基因的志愿者捐赠者的血浆转化生长因子β1蛋白水平来验证这一假设。 血管紧张素转换酶基因ACEALU插入/缺失(INS/Del)突变也与再生障碍性贫血相关(p=0.001)。由于ACE基因中有70多个单核苷酸多态(SNPs)，因此不可能区分INS/Del本身是影响疾病的致病途径，还是通过连锁不平衡追踪致病部位。我们已经完成了FSGS患者和对照的ACE基因测序，以确定单倍型结构，确定与INS/Del连锁不平衡的SNPs，并确定引起FSGS的单倍型等位基因。这项研究还应该深入了解ACE等位基因在高血压中的作用，高血压是影响再生障碍性贫血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.