Bleomycin-induced pulmonary fibrosis susceptibility genes in AcB/BcA recombinant congenic mice.
The genetic basis of susceptibility to pulmonary fibrosis is largely unknown. Initially, in this study, loci regulating the response of bleomycin-induced pulmonary fibrosis were mapped using a set of recombinant congenic strains bred from pulmonary fibrosis-resistant A/J and susceptible C57BL/6J (B6) mice. Linkage was identified (logarithm of the odds score = 4.9) on chromosome 9, and other suggestive loci were detected. The putative loci included alleles from both the B6 and A/J strains as increasing the fibrosis response of congenic mice. Gene expression analysis with microarrays revealed 3,304 genes or expressed sequence tags to be differentially expressed (P < 0.01) in lung tissue between bleomycin-treated B6 and A/J mice, and 246 of these genes mapped to potential susceptibility loci. Pulmonary genes differentially expressed between bleomycin-treated B6 and A/J mice included those of heparin binding and extracellular matrix deposition pathways. A review of available genomic sequences revealed 809 (43% of total) genes in the linkage intervals to have variations predicted to alter the encoded proteins or their regulation, 68 (8.4%) of which were also differentially expressed. Genomic approaches were combined to produce a set of candidate genes that may influence susceptibility to bleomycin-induced pulmonary fibrosis in the A/J:B6 mouse model.
Lemay
Anne-Marie
AM
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Haston
Christina K
CK
D000483:Alleles; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology*; D002874:Chromosome Mapping; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D016678:Genome; D023281:Genomics; D008126:Lod Score; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D040641:Quantitative Trait Loci; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D000903:Antibiotics, Antineoplastic; D011994:Recombinant Proteins; D001761:Bleomycin