Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation

BMC Genomics, Feb 2013

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. Conclusion 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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.biomedcentral.com/content/pdf/1471-2164-14-127.pdf

Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation

BMC Genomics Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation Scott E Levison 0 Paul Fisher Jenny Hankinson Leo Zeef Steve Eyre William E Ollier John T McLaughlin 0 Andy Brass Richard K Grencis Joanne L Pennock 0 0 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 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. Conclusion: 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. Trichuris muris; Colitis; Genetic susceptibility; Cdcs1; Crohn's - Background Many diseases result from the complex interaction of environmental and genetic factors (e.g. Crohns disease, diabetes mellitus) [1,2]. Phenotypic expression is influenced by multiple genes, which individually may increase or decrease the probability of disease development. Gene variation and gene-gene interactions, additionally results in non-linear contributions to phenotypic variation. Discovering the genetic architecture of complex traits thus represents a true challenge [3] and requires collaborative multi-disciplinary investigation and a variety of experimental approaches [4,5]. The exploration of new animal models of colitis with well-defined phenotypes and homology to human pathology, provide a comparative approach to refine biological discoveries for subsequent human translation. Trichuris muris, a natural intestinal parasite of mice has been extensively studied as a model for human whipworm (Trichuris trichiura) infection. In dissecting the immune response to Trichuris infection, a paradigm of resistance and susceptibility to chronic colonic inflammation has emerged [6]. Following the ingestion of parasite ova, acute colitis develops in all mice, but it is the genetic composition of mouse strain which dictates the presence of colitis. BALB/c mice mount immunemediated TH2 dependent parasite expulsion (IL4, IL5 and IL13 expression) [6,7] with full resolution within 20 days. Conversely AKR mice sustain a chronic Trichuris infection, respond with a TH1 immune response (IFN, IL12), and subsequent establishment of colitis [8]. These polarized outcomes occur despite identical treatment and conditioning, and are almost certainly determined by host genetic variation. Importantly, we have recently characterised differences in colonic tissue transcription between susceptible and resistant mice and demonstrated phenotypic, immunological and biological pathway homology to human Crohns disease [9]. These data present T. muris infection not as an aetiological factor in the pathogenesis of Crohns disease, nor solely a model of infection but as a viable and relevant colitis model to in (...truncated)


This is a preview of a remote PDF: http://www.biomedcentral.com/content/pdf/1471-2164-14-127.pdf

Scott E Levison, Paul Fisher, Jenny Hankinson, Leo Zeef, Steve Eyre, William E Ollier, John T McLaughlin, Andy Brass, Richard K Grencis, Joanne L Pennock. Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation, BMC Genomics, 2013, pp. 127, 14, DOI: 10.1186/1471-2164-14-127