Human Molecular Genetics, 2002, Vol. 11, No. 16 1855-1863
© 2002 Oxford University Press
Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice
1Department of Experimental Radiation Oncology, 2Department of Experimental Therapeutics, 3Department of Epidemiology and 4Department of Internal Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Received March 25, 2002; Revised June 3, 2002; Accepted June 4, 2002
Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD=17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD=5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11C3H, and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpf1 as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.
* To whom correspondence should be addressed at: Experimental Radiation Oncology, Box 066, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 66, Houston, TX 77030, USA. Tel: +1 7137923424; Fax: +1 7137945369; Email: etravis{at}mdanderson.org
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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