title: Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice.
abstract: OBJECTIVE
  To identify genes which influence the fibrotic response to thoracic cavity radiotherapy, we combined a genome wide single nucleotide polymorphism (SNP) association evaluation of inbred strain response with prior linkage and gene expression data.
  
  
  METHODS
  Mice were exposed to 18Gy whole thorax irradiation and survival, bronchoalveolar cell differential, and histological alveolitis and fibrosis phenotypes were determined. Association analyses were completed with 1.8 million SNPs in single markers and haplotypes.
  
  
  RESULTS
  Nine strains developed significant fibrosis and 11 strains succumbed to alveolitis only or alveolitis with minimal fibrosis. Post irradiation survival time (p<0.001) and bronchoalveolar lavage neutrophil percent (p=0.055) were correlated with extent of alveolitis and were not significantly correlated with fibrosis. Genome wide SNP analysis identified 10 loci as significantly associated with radiation-induced fibrotic lung disease (p<8.41×10(-6); by permutation test), with the most significant SNP within a conserved non-coding region downstream of cell adhesion molecule 1 (Cadm1). Haplotype and SNP analyses performed within previously-identified loci revealed additional genes containing SNPs associated with fibrosis including Slamf6 and Cdkn1a.
  
  
  CONCLUSIONS
  Combining genomic approaches identified variation within specific genes which function in the tissue response to injury as associated with fibrosis following thoracic irradiation in mice.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, PQ, Canada
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paun
authors.forename: Christina K
authors.initials: CK
authors.lastname: Haston
mesh_terms: D000465:Algorithms; D000818:Animals; D015870:Gene Expression / Q000528:radiation effects; D056426:Genetic Loci / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D016678:Genome / Q000528:radiation effects*; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D051379:Mice; D008815:Mice, Inbred Strains; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017564:Radiation Pneumonitis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013909:Thorax / Q000528:radiation effects*