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。在这项研究中，我们收集了四组非裔美国人：1)特发性FSGS(n=195)；2)捐赠者对照组(n=393)；3)HIV相关FSGS(n=53)；以及4)HIV对照组(n=244)。我们还收集了131名患有FSGS的欧洲美国人和282名正常捐赠者的欧洲美国人作为对照组。欧美研究小组中的所有人都检测出HIV-1感染的风险因素为阴性或缺乏。 我们正在使用候选基因方法来识别与FSGS表型相关的标记。NPHS2基因突变与肾病综合征有关，包括局灶节段性肾小球硬化。NPHS2编码Podocin，这是一种仅在肾小球足细胞上表达的蛋白质。Podocin是一种完整的膜蛋白，位于足部与裂隙隔膜相邻的突起上，被认为在影响液压流动和蛋白质从血浆空间进入尿腔的过程中发挥关键作用。Podocin与其他足细胞蛋白相互作用，包括向质膜内的脂筏和CD2AP招募neparin。 已对病例和对照进行了12个NPHS2单核苷酸多态(SNPs)的基因分型。由于FSGS与非裔美国人中的HIV-1有关，我们分别分析了HIV组和HIV+组，然后将这两组结合起来，以分析所有FSGS病例与对照组。比较病例和对照组的等位基因和基因型频率，评估NPHS2 SNP等位基因与FSGS的相关性。在非裔美国人中，1个SNP与FSGS相关(P=0.015)，在非裔美国人中以病例对照组为主(P=0.008)，在欧洲裔美国人中有2个SNP与FSGS相关(P=0.036)。已经进行了单倍型分析，在非裔美国人中，有一种单倍型似乎具有保护性，而在欧洲裔美国人中，另一种单倍型似乎增加了对FSGS的易感性。分析还显示，单倍型与FSGS的发病年龄之间存在很强的相关性。 最近，我们报道了Wilms‘s肿瘤基因WTI的变异与非裔美国人的FSGS有关。Wilms‘s肿瘤基因对肾脏发生和性腺生长很重要，该基因的突变会导致Denys-Drash和Frasier综合征，其特征是肾小球瘢痕形成。紧靠Wilms‘s肿瘤基因上游的是WIT1，它与WT1具有相同的启动子。

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 four groups of African Americans in this study: 1) idiopathic FSGS (n=195); 2) donor controls (n=393); 3) HIV-associated FSGS (n=53); and 4) HIV controls (n=244). We also accrued 131 European Americans with FSGS and 282 normal donor European Americans as a control group. All individuals in the European American study group tested negative or lacked risk factors for HIV-1 infection. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. Mutations in NPHS2 have been associated with nephrotic syndrome, including focal segmental glomerulosclerosis. NPHS2 encodes podocin, a protein expressed exclusively on the glomerular podocyte. Podocin is an integral membrane protein that is located on the foot processes adjacent to the slit diaphragms that are postulated to play a critical role in influencing hydraulic flow and protein exit from the plasma space into the urinary space. Podocin interacts with other podocyte proteins, including recruiting nephrin to lipid rafts within the plasma membrane and CD2AP. Cases and controls have been genotyped for twelve NPHS2 single nucleotide polymorphisms (SNPs). As FSGS is associated with HIV-1 in African Americans we analysed the HIV- group and the HIV+ group separately and then combined both groups in order to analyze all FSGS cases versus controls. The association between NPHS2 SNP alleles and FSGS was evaluated comparing allele and genotype frequencies between cases and controls. One SNP was associated with FSGS in the HIV+ group (P=0.015) and the case control group (regardless of HIV status) (P=0.008) for the dominant model in African Americans and two other SNPs (P=0.036 were associated with FSGS in European Americans. Haplotype analyses have been performed and in African Americans there is one haplotype that appears to be protective whereas in European Americans a different haplotype appears to increase susceptibility to FSGS. Analyses also revealed a strong association between haplotype and age of FSGS onset. Recently we reported that variants in the Wilms' tumor gene WTI are associated with FSGS in African Americans. The Wilms' tumor gene is important for nephrogenesis and gonadal growth and mutations within the gene cause Denys-Drash and Frasier syndromes, which are characterized by glomeruli scarring. Immediately upstream to the Wilms' tumor gene is the WIT1 that shares a promoter with WT1.