Gharavi Ali G, Ahmad Tariq, Wong Robert D, Hooshyar Roozbeh, Vaughn Janene, Oller Sarah, Frankel Rachelle Z, Bruggeman Leslie A, D'Agati Vivette D, Klotman Paul E, Lifton Richard P
Howard Hughes Medical Institute and Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2488-93. doi: 10.1073/pnas.0308649100.
HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection with distinct pathologic features. Introduction of the HIV-1 genome into mice results in a renal disease with all of the histologic and clinical hallmarks of HIVAN on the FVB/N genetic background (TgFVB). We assessed the influence of genetic background on the development or progression of HIVAN by making F1 hybrids of TgFVB with five other inbred strains (CBA, DBA/2, CAST/Ei, C3H/He, BALB/c) and determining phenotypes relevant to renal failure among transgenic offspring (histology, blood urea nitrogen, proteinuria, serum albumin, and serum cholesterol). We found striking variation in phenotypes among F1s, ranging from severe renal disease to no renal disease whatsoever (P<0.001 for ANOVA across all groups). To map genes responsible for this variation, we produced a backcross of TgFVB/CAST F1 x TgFVB. By genome-wide analysis of linkage in 185 heterozygous transgenic backcross mice, we identified a locus on chromosome 3A1-3, HIVAN1, that showed highly significant linkage to renal disease [logarithm of odds (lod) score 4.9 at D3Mit203, accounting for 15% of the variance in renal disease]. Other loci on chromosomes 11, 14, and 16 were suggestive of linkage to renal disease, and a locus on chromosome 9 influenced serum cholesterol but not nephropathy. Interestingly, HIVAN1 is syntenic to human chromosome 3q25-27, an interval showing suggestive evidence of linkage to various nephropathies. These findings demonstrate a strong genetic influence on HIVAN and demonstrate a major renal disease susceptibility locus on mouse chromosome 3A1-3.
HIV-1相关性肾病（HIVAN）是HIV-1感染的一种主要并发症，具有独特的病理特征。将HIV-1基因组导入小鼠后，在FVB/N遗传背景（TgFVB）下会导致一种具有HIVAN所有组织学和临床特征的肾脏疾病。我们通过将TgFVB与其他五个近交系（CBA、DBA/2、CAST/Ei、C3H/He、BALB/c）杂交产生F1杂种，并确定转基因后代中与肾衰竭相关的表型（组织学、血尿素氮、蛋白尿、血清白蛋白和血清胆固醇），来评估遗传背景对HIVAN发生或进展的影响。我们发现F1代的表型存在显著差异，从严重肾病到无肾病（所有组方差分析P<0.001）。为了定位导致这种差异的基因，我们构建了TgFVB/CAST F1与TgFVB的回交。通过对185只杂合转基因回交小鼠进行全基因组连锁分析，我们在3A1 - 3号染色体上确定了一个位点HIVAN1，该位点与肾脏疾病显示出高度显著的连锁关系[在D3Mit203处的优势对数（lod）分数为4.9，占肾脏疾病方差的15%]。11号、14号和16号染色体上的其他位点提示与肾脏疾病存在连锁关系，9号染色体上的一个位点影响血清胆固醇但不影响肾病。有趣的是，HIVAN1与人3号染色体q25 - 27区域同线，该区域显示出与各种肾病存在连锁关系的提示性证据。这些发现表明遗传因素对HIVAN有强烈影响，并在小鼠3A1 - 3号染色体上证明了一个主要的肾脏疾病易感位点。
