Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3.
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.
Howard Hughes Medical Institute and Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Ali G
AG
Gharavi
Tariq
T
Ahmad
Robert D
RD
Wong
Roozbeh
R
Hooshyar
Janene
J
Vaughn
Sarah
S
Oller
Rachelle Z
RZ
Frankel
Leslie A
LA
Bruggeman
Vivette D
VD
D'Agati
Paul E
PE
Klotman
Richard P
RP
Lifton
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D017931:DNA Primers; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D015497:HIV-1 / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D010641:Phenotype; D011110:Polymorphism, Genetic
D017931:DNA Primers; D005819:Genetic Markers