Genetics of Renal Disease in African Americans

非裔美国人肾病遗传学

• 批准号: 6950627
• 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/6950627
• 关键词: African American; HIV infections; cardiovascular disorder risk; caucasian American; clinical research; disease /disorder etiology; gene environment interaction; gene expression; genetic mapping; genetic markers; genetic polymorphism; genetic screening; genetic susceptibility; glomerulosclerosis; health disparity; human genetic material tag; human subject; hypertension; patient oriented research; racial /ethnic difference

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.

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，以及 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。我们收集了 236 名患有 FSGS 的非洲裔美国人和 114 名白人，259 名感染 HIV 至少八年但仍保持正常肾功能的静脉注射吸毒者，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，已对病例和对照中涉及炎症反应或纤维化的双等位候选基因进行了基因分型。我们对所有患者的大约 40 个位点的一种或多种多态性进行了基因分型，包括许多趋化因子和趋化因子受体、细胞因子和肾素-血管紧张素-TGFb 轴的成分。我们观察到 Alu 插入等位基因 (I) 与非裔美国人 FSGS 风险增加有关。 II 基因型在黑人 FSGS 病例中比未受影响的对照中出现的频率明显更高。对于非裔美国人受试者，与 HIV 血清阳性正常肾脏受试者相比，Alu II 基因型在 FSGS 患者中更为常见（OR=2.0，p=0.003）。有趣的是，对于白种人受试者，存在相反方向的趋势，与献血者相比，FSGS 患者中 II 基因型的频率较低（OR 0.56，P=0.08）。由于 ACE 基因中有超过 70 个已识别的单核苷酸多态性 (SNP)，因此无法辨别 ins/del 本身是否影响疾病的因果途径，或者是否通过连锁不平衡追踪因果位点。我们已经完成了 400 个 FSGS 病例和对照的 ACE 基因测序，以确定单倍型结构，识别与 ins/del 连锁不平衡的 SNP，并识别致病单倍型等位基因。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 的影响尤为严重。 在 TGFb1 基因 (TGFB1) 中发现了一个小发现，它是一种公认​​的促纤维化细胞因子 [综述参考文献 19]。与献血者相比，纯合野生型单倍型（-800 处的 G、-509 处的 C、10 号密码子的 L 和 25 号密码子的 R）在非洲裔美国人 HIV 血清阴性 FSGS 受试者中更为常见（OR 2.0，P=0.03）。与 HIV 血清阳性正常肾脏受试者相比，非裔美国人 HIV 相关 FSGS 患者没有类似的趋势。