Genetics of Renal Disease in African Americans

局灶节段性肾小球硬化症（FSGS）的特征在于纤维化蛋白在肾小球中的积累，最初仅影响一些肾小球（局灶性）并且仅影响受影响肾小球的节段性部分。FSGS包括以下实体：1）特发性FSGS，包括特别侵袭性的塌陷变体; 2）HIV相关的FSGS;和3）与肾单位质量减少相关的超滤FSGS。最普遍接受的发病机制模型提出，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。最近的研究结果支持了这一模型，即家族性FSGS可能与足细胞表达基因WT-1、辅肌动蛋白4和podocin的突变有关。非洲裔美国人发生特发性FSGS的风险是正常人的3倍，HIV相关FSGS的风险增加18倍，尽管大多数患者缺乏FSGS家族史。这些观察结果表明，增加的易感性的遗传基础，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、SV 40或HIV-1感染）后易患FSGS。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。在本研究中，我们收集了四组非裔美国人：1）特发性FSGS（n=195）; 2）供体对照（n=393）; 3）HIV相关FSGS（n=53）;和4）HIV对照（n=244）。我们还收集了131名患有FSGS的欧洲裔美国人和282名正常供体欧洲裔美国人作为对照组。在欧洲美国研究组的所有个人测试阴性或缺乏HIV-1感染的危险因素。 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。NPHS 2突变与肾病综合征有关，包括局灶节段性肾小球硬化。NPHS 2编码podocin，一种仅在肾小球足细胞上表达的蛋白质。Podocin是一种整合的膜蛋白，其位于与狭缝隔膜相邻的足突上，假定狭缝隔膜在影响液压流和蛋白质从血浆空间离开进入泌尿空间中中起关键作用。Podocin与其他足细胞蛋白相互作用，包括将nephrin募集到质膜内的脂筏和CD 2AP。 病例组和对照组已进行了12个NPHS 2单核苷酸多态性（SNP）的基因分型。由于FSGS与非裔美国人中的HIV-1相关，我们分别分析了HIV-组和HIV+组，然后将两组合并，以分析所有FSGS病例与对照组。比较病例组和对照组的等位基因和基因型频率，评估NPHS 2 SNP等位基因与FSGS之间的关联。在非裔美国人中，一个SNP与HIV+组（P=0.015）和病例对照组（不考虑HIV状态）（P=0.008）中的FSGS相关，而另外两个SNP（P=0.036）与欧洲裔美国人中的FSGS相关。已经进行了单倍型分析，在非洲裔美国人中，有一种单倍型似乎具有保护作用，而在欧洲裔美国人中，不同的单倍型似乎增加了对FSGS的易感性。分析还揭示了单倍型和FSGS发病年龄之间的强相关性。 最近，我们报道了Wilms肿瘤基因WTI的变异与非裔美国人的FSGS相关。肾母细胞瘤基因对于肾发生和性腺生长是重要的，并且该基因内的突变引起Denys-Drash和Frasier综合征，其特征在于肾小球瘢痕形成。紧邻Wilms肿瘤基因上游的是WIT 1，其与WT 1共享启动子。

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.