title: Interaction of Crohn's disease susceptibility genes in an Australian paediatric cohort.
abstract: Genetic susceptibility is an important contributor to the pathogenesis of Crohn's disease (CD). We investigated multiple CD susceptibility genes in an Australian paediatric onset CD cohort. Newly diagnosed paediatric onset CD patients (n = 72) and controls (n = 98) were genotyped for 34 single nucleotide polymorphisms (SNPs) in 18 genetic loci. Gene-gene interaction analysis, gene-disease phenotype analysis and genetic risk profiling were performed for all SNPs and all genes. Of the 34 SNPs analysed, four polymorphisms on three genes (NOD2, IL23R, and region 3p21) were significantly associated with CD status (p<0.05). All three CD specific paediatric polymorphisms on PSMG1 and TNFRSF6B showed a trend of association with p<0.1. An additive gene-gene interaction involving TLR4, PSMG1, TNFRSF6B and IRGM was identified with CD. Genes involved in microbial processing (TLR4, PSMG1, NOD2) were significantly associated either at the individual level or in gene-gene interactive roles. Colonic disease was significantly associated with disease SNP rs7517847 (IL23R) (p<0.05) and colonic and ileal/colonic disease was significantly associated with disease SNP rs125221868 (IBD5) and SLC22A4 & SLC22A4/5 variants (p<0.05). We were able to demonstrate genetic association of several genes to CD in a paediatric onset cohort. Several of the observed associations have not been reported previously in association with paediatric CD patients. Our findings demonstrate that CD genetic susceptibility in paediatric patients presents as a complex interaction between numerous genes.
authors.affiliation: Enteric Virus Group, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. josef.wagner@mcri.edu.au
authors.forename: Josef
authors.initials: J
authors.lastname: Wagner
authors.forename: Winnie H
authors.initials: WH
authors.lastname: Sim
authors.forename: Justine A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Eng K
authors.initials: EK
authors.lastname: Ong
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Catto-Smith
authors.forename: Donald J S
authors.initials: DJ
authors.lastname: Cameron
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Bishop
authors.forename: Carl D
authors.initials: CD
authors.lastname: Kirkwood
mesh_terms: D001315:Australia; D016009:Chi-Square Distribution; D002648:Child; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D004843:Epistasis, Genetic; D019204:GTP-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008565:Membrane Proteins / Q000235:genetics; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000235:genetics; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: C515500:IL23R protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009124:Muscle Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D027701:Organic Cation Transport Proteins; C410584:PSMG1 protein, human; D018123:Receptors, Interleukin; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; C495345:TLR4 protein, human; C505911:TNFRSF6B protein, human; D051197:Toll-Like Receptor 4; D019204:GTP-Binding Proteins; C513539:IRGM protein, human