Genetics of Renal Disease in African Americans

非裔美国人肾病遗传学

• 批准号: 7291760
• 负责人: CHERYL ANN WINKLER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291760
• 关键词: Genetics; Renal; Disease; African; Americans

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.

局灶节段性肾小球硬化症 (FSGS) 的特征是肾小球中纤维化蛋白的积累，最初仅影响部分肾小球（局灶性），并且仅影响受影响肾小球的节段部分。 FSGS 包括以下实体：1) 特发性 FSGS，包括特别侵袭性的崩溃变体； 2) HIV相关的FSGS； 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疤痕形成的过程。最近的研究结果支持了该模型，即家族性 FSGS 可能与足细胞表达基因 WT-1、肌动蛋白 4 和 podocin 的突变有关。尽管大多数患者没有 FSGS 家族史，但非洲裔美国人患特发性 FSGS 的风险是其三倍，患 HIV 相关 FSGS 的风险增加 18 倍。这些观察结果表明易感性增加有遗传基础，但相关位点尚未确定。 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（例如细小病毒 B19、SV40 或 HIV-1 感染）后易患 FSGS。与 NIDDK 肾脏疾病科合作，一项涉及 13 个校外站点的多中心研究已经启动。我们在这项研究中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相关的FSGS (n=53)； 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 名正常捐赠者欧洲裔美国人作为对照组。欧美研究组中的所有个体的检测结果均呈阴性或缺乏 HIV-1 感染的危险因素。 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 突变与肾病综合征相关，包括局灶节段性肾小球硬化症。 NPHS2 编码足蛋白，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，位于邻近狭缝隔膜的足突上，推测狭缝隔膜在影响水流和蛋白质从血浆空间进入泌尿空间方面发挥着关键作用。 Podocin 与其他足细胞蛋白相互作用，包括将去氧肾上腺素募集到质膜和 CD2AP 内的脂筏上。 已对病例和对照的 12 个 NPHS2 单核苷酸多态性 (SNP) 进行了基因分型。由于 FSGS 与非裔美国人中的 HIV-1 相关，因此我们分别分析了 HIV 组和 HIV+ 组，然后将两组合并起来，以便分析所有 FSGS 病例与对照。比较病例和对照之间的等位基因和基因型频率，评估 NPHS2 SNP 等位基因和 FSGS 之间的关联。一个 SNP 与 HIV+ 组 (P=0.015) 和病例对照组（无论 HIV 状态如何）(P=0.008) 中的 FSGS 相关，是非洲裔美国人的主导模型，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性，而在欧洲裔美国人中，有一种不同的单倍型。 单倍型似乎增加了 FSGS 的易感性。分析还揭示了单倍型与 FSGS 发病年龄之间的密切相关性。 最近我们报道称，威尔姆斯氏肿瘤基因 WTI 的变异与非裔美国人的 FSGS 相关。维尔姆斯氏肿瘤基因对于肾发生和性腺生长很重要，该基因内的突变会导致 Denys-Drash 和 Frasier 综合征，其特征是肾小球疤痕。紧邻 Wilms 肿瘤基因上游的是 WIT1，它与 WT1 共享一个启动子。