Genetics of Renal Disease in African Americans

非裔美国人肾病遗传学

• 批准号: 6433185
• 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/6433185
• 关键词: African American; HIV infections; disease /disorder proneness /risk; genetic mapping; genetic markers; glomerulosclerosis; histocompatibility gene; human genetic material tag; human population genetics; racial /ethnic difference

Focal segmental glomerulosclerosis (FSGS) occurs in an idiopathic form and in association with HIV infection, both of which are more common among African-Americans (AA). The pathogenesis of FSGS remains an unknown and no effective therapy has been demonstrated. We hypothesize that a gene or genes, present in people of African descent, predisposes to FSGS following exposure to particular environmental factors such as HIV infection. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 200 AA with FSGS and 210 intravenous drug users who have been infected with HIV for at least eight years but retain normal kidney function. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, 258 cases and controls have been genotyped for 22 diallelic candidate genes. Two polymorphic sites in the promoter and first exon of the transforming growth factor beta 1(TGFb1) gene have been shown by this study to be associated with the FSGS phenotype. Analysis of the TGF(TGFb1) alleles provides evidence that the wildtype (ancestral) haplotype is associated with increased risk of FSGS, possibly by the up-regulation of TGF beta 1 protein. The alu insertion/deletion mutation in the angiotensin converting enzyme gene ACE is also associated with FSGS (p=0.001). As there are more than 70 identified SNPs in the ACE gene, it is not possible to discern if this mutation is itself affecting the causal pathway of the disease or if the insertion is in linkage disequilibrium with an as yet undetected susceptibility locus. We are currently using haplotype analysis and sequence analysis to resolve this uncertainty.

局灶节段性肾小球硬化症 (FSGS) 以特发性形式发生，并与 HIV 感染相关，这两种情况在非裔美国人 (AA) 中更为常见。 FSGS 的发病机制仍然未知，并且尚未证明有效的治疗方法。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 HIV 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。我们通过 FSGS 积累了 200 AA，并为 210 名静脉吸毒者积累了 HIV 感染至少八年但仍保持正常肾功能的人。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 258 个病例和对照的 22 个双等位候选基因进行了基因分型。 本研究表明转化生长因子β1（TGFb1）基因的启动子和第一个外显子中的两个多态性位点与FSGS表型相关。 TGF(TGFb1) 等位基因的分析提供了证据，表明野生型（祖先）单倍型与 FSGS 风险增加相关，可能是通过 TGF beta 1 蛋白的上调实现的。 血管紧张素转换酶基因 ACE 中的 alu 插入/缺失突变也与 FSGS 相关 (p=0.001)。由于 ACE 基因中有超过 70 个已识别的 SNP，因此无法辨别该突变本身是否影响疾病的因果途径，或者插入是否与尚未检测到的易感位点处于连锁不平衡。我们目前正在使用单倍型分析和序列分析来解决这种不确定性。