title: Association analysis reveals genetic variation altering bleomycin-induced pulmonary fibrosis in mice.
abstract: Pulmonary fibrosis is a disease of significant morbidity, with an incompletely defined genetic basis. Here, we combine linkage and association studies to identify genetic variations associated with pulmonary fibrosis in mice. Mice were treated with bleomycin by osmotic minipump, and pulmonary fibrosis was histologically assessed 6 weeks later. Fibrosis was mapped in C57BL6/J (fibrosis-susceptible) × A/J (fibrosis-resistant) F2 mice, and the major identified linkage intervals were evaluated in consomic mice. Genome-wide and linkage-interval genes were assessed for their association with fibrosis, using phenotypic data from 23 inbred strains and the murine single-nucleotide polymorphism map. Susceptibility to pulmonary fibrosis mapped to a locus on chromosome 17, which was verified with consomic mice, and to three additional suggestive loci that may interact with alleles on chromosome 17 to affect the trait in F2 mice. Two of the loci, including the region on chromosome 17, are homologous to previously mapped loci of human idiopathic fibrosis. Of the 23 phenotyped murine strains, four developed significant fibrosis, and the majority presented minimal disease. Genome-wide and linkage region-specific association studies revealed 11 pulmonary expressed genes (including the autophagy gene Cep55, and Masp2, which is a complement component) to contain polymorphisms significantly associated with bleomycin-induced fibrotic lung disease. In conclusion, genomic approaches were used to identify linkage intervals and specific genetic variations associated with pulmonary fibrosis in mice. The common loci and similarities in phenotype suggest these findings to be of relevance to clinical pulmonary fibrosis.
authors.affiliation: Meakins-Christie Laboratories, McGill University, 3626 St. Urbain, Montreal, PQ, H2X 2P2 Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paun
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lemay
authors.forename: Tomasz G
authors.initials: TG
authors.lastname: Tomko
authors.forename: Christina K
authors.initials: CK
authors.lastname: Haston
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011110:Polymorphism, Genetic; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D001761:Bleomycin