Genetics of Renal Disease in African Americans

局灶性节段性肾小球硬化(FSGS)的特征是纤维化蛋白在肾小球内积聚，最初仅影响部分肾小球(局灶性)，仅影响受影响肾小球的一部分。FSGS包括以下实体：1)特发性FSGS，包括一种特别具有侵袭性的塌陷变异体；2)HIV相关FSGS；以及3)与肾单位质量减少相关的高滤过性FSGS。最普遍接受的发病机制模型认为，足细胞(内脏肾小球上皮细胞)的损伤启动了导致肾小球瘢痕形成的过程。最近的研究发现，家族性FSGS与足细胞表达基因WT-1、Actinin 4和Podocin的突变有关，这一模型得到了支持。尽管大多数患者没有FSGS家族史，但非裔美国人患特发性FSGS的风险是前者的三倍，与HIV相关的FSGS的风险增加了18倍。这些观察结果表明，易感性增加是有遗传基础的，但相关的基因座尚未确定。我们假设，非洲人后裔中存在的一个或多个基因，在暴露于特定环境因素(如细小病毒B19、SV40或HIV-1感染)后易患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。我们收集了236名患有FSGS的非裔美国人和114名高加索人，259名感染艾滋病毒至少8年但肾功能正常的静脉注射吸毒者，以及125名正常捐赠者对照。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，病例和对照已经对参与炎症反应或纤维化的双等位候选基因进行了基因分型。我们已经对所有患者进行了大约40个基因座上一个或多个基因多态的基因分型，包括一些趋化因子和趋化因子受体，细胞因子，以及肾素-血管紧张素-TGFb轴的组成部分。我们观察到，在非裔美国人中，Alu插入等位基因(I)与FSGS风险增加有关。在黑人FSGS患者中，II基因型的频率明显高于未受影响的对照组。在非裔美国人受试者中，与HIV血清阳性的正常肾脏受试者相比，Alu II基因在FSGS患者中更常见(OR=2.0p=0.003)。有趣的是，高加索人群的情况则相反，FSGS患者中II基因频率低于献血者(OR 0.56，P=0.08)。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400例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，并确定致病的单倍型等位基因。这项研究还应该深入了解ACE等位基因在高血压中的作用，高血压是一个重要的心血管危险因素，对AA的影响不成比例。 在TGFb1基因(TGFB1)中发现了一个微小的发现，它是一种公认的促纤维化细胞因子[回顾参考文献19]。纯合子野生型单倍型(G在-800，C在-509，L在第10密码子，R在第25密码子)在非裔美国人HIV血清阴性FSGS患者中比献血者更常见(OR2.0，P=0.03)。与HIV血清阳性的正常肾脏受试者相比，非裔美国人HIV相关的FSGS患者没有类似的趋势。

Focal segmental glomerulosclerosis (FSGS) is characterized by the accumulation of fibrotic proteins in glomeruli, initially affecting only some glomeruli (focal) and affecting only a segmental portion of the affected glomeruli. FSGS includes the follow entities: 1) idiopathic FSGS, including a particularly aggressive collapsing variant; 2) HIV-associated FSGS, and 3) hyperfiltration FSGS associated with reduced nephron mass. The most commonly accepted model of pathogenesis proposes that injury to the podocyte (the visceral glomerular epithelial cell) initiates a process that leads to glomerular scarring. This model is supported by recent findings that familial FSGS can be associated with mutations in podocyte-expressed genes WT-1, actinin 4, and podocin. African-Americans are at a three-fold risk of developing idiopathic FSGS, and at an 18-fold increased risk for HIV-associated FSGS, although most patients lack a family history of FSGS. These observations have suggested a genetic basis for increased susceptibility, but the relevant loci have not been identified. We hypothesize that a gene or genes present in people of African descent, predisposes to FSGS following exposure to particular environmental factors such as infection by parvovirus B19, SV40 or HIV-1. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 236 African-Americans and 114 caucasians with FSGS, 259 intravenous drug users who have been infected with HIV for at least eight years but retain normal kidney function, and 125 normal donor controls. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, cases and controls have been genotyped for diallelic candidate genes involved in inflammatory response or fibrosis. We have genotyped all patients for one or more polymorphisms at approximately 40 loci, including a number of chemokines and chemokine receptors, cytokines, and components of the renin-angiotensin -TGFb axis. We have observed an association with the Alu insertion allele (I) with increased risk for FSGS in African-Americans. The II genotype was significantly more frequent among black FSGS cases than in unaffected controls. For the Among African-American subjects, the Alu II genotype was more common among FSGS patients compared to HIV-seropositive normal kidney subjects (OR=2.0, p=0.003). Interestingly, for caucasian subjects there was trend in the opposite direction, with the II genotype less frequent among FSGS patients compared with blood donors (OR 0.56, P=0.08). 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 400 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 disproportionately affecting AA. A minor finding was seen in the TGFb1 gene (TGFB1), which is a well recognized pro-fibrotic cytokine [Review reference 19]. The homozygous wild type haplotype (G at -800, C at -509, L at codon 10, and R at codon 25) was more common among African-American HIV-seronegative FSGS subjects compared with blood donors (OR 2.0, P=0.03). There was no similar trend for African-American HIV-associated FSGS patients compared to HIV-seropositive normal kidney subjects.