GENETICS OF RENAL DISEASE IN AFRICAN AMERICANS

局灶性节段性肾小球硬化(FSGS)以特发性形式发生，并与HIV感染相关，两者在非裔美国人(AA)中更为常见。FSGS的发病机制尚不清楚，也没有有效的治疗方法被证明。我们假设，非洲人后裔中存在的一个或多个基因，在暴露于特定的环境因素(如艾滋病毒感染)后，容易患上FSGS。在与NIDDK肾脏病科的合作下，已经启动了对13个壁外部位的多中心研究。我们已经积累了176名患有FSGS的AA患者和200名感染HIV至少8年但肾功能正常的静脉吸毒者。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，我的团队已经对258例患者和对照的22个双等位候选基因进行了基因分型。血管紧张素转换酶基因ACE的插入/缺失突变和血管紧张素转换酶基因的插入/缺失突变均与FSGS相关。使用隐性遗传模型(优势比2.57，p=0.007)，血管紧张素转换酶基因的插入与发生FSGS的风险增加高度相关。由于ACE基因中有70多个已识别的SNPs，因此不可能辨别该突变本身是否影响疾病的致病途径，或者该插入是否与尚未检测到的易感基因连锁不平衡。我们目前正在使用单倍型分析来解决这种不确定性。-艾滋病毒，局灶性节段性肾小球硬化，肾脏疾病，序列分析，-人体组织，液体，细胞等

Focal segmental glomerulosclerosis (FSGS)occurs in an idiopathic form and in associationwith HIV infection, both of whichare more common among African-Americans (AA). Thepathogenesis of FSGS remains an unknown and noeffective therapy has been demonstrated. Wehypothesize that a gene or genes, present in people of African descent, predisposes to FSGS following exposureto particular environmental factors such asHIV infection. In collaborationwith the Kidney Disease Section, NIDDK, amulticenter study with 13 extramural sites hasbeen initiated. We have accrued 176 AA withFSGS and 200 intravenous drug users who have beeninfected with HIV for at least eight years butretain normal kidney function. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, my group has genotyped 258 cases and controls for 22 diallelic candidate genes. Polymorphic sites in the 3UTR of APJ encoding the angiotensis receptor- like protein 1, a member of the 7 trans-membrane G-coupled receptor family, and the insertion/deletion mutation of angiotensin converting enzyme gene ACE have each been shown to be associated with FSGS. The ACE insertion was highly associated for increased risk of developing FSGS using a recessive genetic model (odds ratio 2.57, p=.007). 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 to resolve this uncertainty. - HIV, Focal segmental glomerulosclerosis, Kidney disease, Sequence analysis, - Human Tissues, Fluids, Cells, etc.