title: Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation.
abstract: BACKGROUND
  Genetic susceptibility to colonic inflammation is poorly defined at the gene level. Although Genome Wide Association studies (GWAS) have identified loci in the human genome which confer susceptibility to Inflammatory Bowel Disease (Crohn's and Ulcerative Colitis), it is not clear if precise loci exist which confer susceptibility to inflammation at specific locations within the gut e.g. small versus large intestine. Susceptibility loci for colitis in particular have been defined in the mouse, although specific candidate genes have not been identified to date. We have previously shown that infection with Trichuris muris (T. muris) induces chronic colitis in susceptible mouse strains with clinical, histological, and immunological homology to human colonic Crohn's disease. We performed an integrative analysis of colitis susceptibility, using an F2 inter-cross of resistant (BALB/c) and susceptible (AKR) mice following T. muris infection. Quantitative Trait Loci (QTL), polymorphic and expression data were analysed alongside in silico workflow analyses to discover novel candidate genes central to the development and biology of chronic colitis.
  
  
  RESULTS
  7 autosomal QTL regions were associated with the establishment of chronic colitis following infection. 144 QTL genes had parental strain SNPs and significant gene expression changes in chronic colitis (expression fold-change ≥ +/-1.4). The T. muris QTL on chromosome 3 (Tm3) mapped to published QTL in 3 unrelated experimental models of colitis and contained 33 significantly transcribed polymorphic genes. Phenotypic pathway analysis, text mining and time-course qPCR replication highlighted several potential cis-QTL candidate genes in colitis susceptibility, including FcgR1, Ptpn22, RORc, and Vav3.
  
  
  CONCLUSIONS
  Genetic susceptibility to induced colonic mucosal inflammation in the mouse is conserved at Tm3 and overlays Cdcs1.1. Genes central to the maintenance of intestinal homeostasis reside within this locus, implicating several candidates in susceptibility to colonic inflammation. Combined methodology incorporating genetic, transcriptional and pathway data allowed identification of biologically relevant candidate genes, with Vav3 newly implicated as a colitis susceptibility gene of functional relevance.
authors: Gastrointestinal Sciences, Institute of Inflammation and Repair, Faculty of Medicine and Human Sciences, University of Manchester, 4.004 AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Scott E
authors: SE
authors: Levison
authors: Paul
authors: P
authors: Fisher
authors: Jenny
authors: J
authors: Hankinson
authors: Leo
authors: L
authors: Zeef
authors: Steve
authors: S
authors: Eyre
authors: William E
authors: WE
authors: Ollier
authors: John T
authors: JT
authors: McLaughlin
authors: Andy
authors: A
authors: Brass
authors: Richard K
authors: RK
authors: Grencis
authors: Joanne L
authors: JL
authors: Pennock
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000469:parasitology; D017238:Genes, Helminth; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D018895:Microsatellite Repeats; D005810:Multigene Family; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014257:Trichuriasis / Q000235:genetics / Q000469:parasitology; D014258:Trichuris / Q000235:genetics* / Q000472:pathogenicity