title: Analysis of candidate colitis genes in the Gdac1 locus of mice deficient in glutathione peroxidase-1 and -2.
abstract: BACKGROUND
  Mice that are deficient for glutathione peroxidases 1 and 2 (GPX) show large variations in the penetrance and severity of colitis in C57BL/6J and 129S1/SvImJ backgrounds. We mapped a locus contributing to this difference to distal chromosome 2 (∼119-133 mbp) and named it glutathione peroxidase-deficiency-associated colitis 1 (Gdac1). The aim of this study was to identify the best gene candidates within the Gdac1 locus contributing to the murine colitis phenotype.
  
  
  RESULTS
  We refined the boundaries of Gdac1 to 118-125 mbp (95% confidence interval) by increasing sample size and marker density across the interval. The narrowed region contains 128 well-annotated protein coding genes but it excludes Fermt1, a human inflammatory bowel disease candidate that was within the original boundaries of Gdac1. The locus we identified may be the Cdcs3 locus mapped by others studying IL10-knockout mice. Using in silico analysis of the 128 genes, based on published colon expression data, the relevance of pathways to colitis, gene mutations, presence of non-synonymous-single-nucleotide polymorphisms (nsSNPs) and whether the nsSNPs are predicted to have an impact on protein function or expression, we excluded 42 genes. Based on a similar analysis, twenty-five genes from the remaining 86 genes were analyzed for expression-quantitative-trait loci, and another 15 genes were excluded.
  
  
  CONCLUSIONS
  Among the remaining 10 genes, we identified Pla2g4f and Duox2 as the most likely colitis gene candidates, because GPX metabolizes PLA2G4F and DUOX2 products. Pla2g4f is a phospholipase A2 that has three potentially significant nsSNP variants and showed expression differences across mouse strains. PLA2G4F produces arachidonic acid, which is a substrate for lipoxygenases and, in turn, for GPXs. DUOX2 produces H(2)O(2) and may control microbial populations. DUOX-1 and -2 control microbial populations in mammalian lung and in the gut of several insects and zebrafish. Dysbiosis is a phenotype that differentiates 129S1/SvImJ from C57BL/6J and may be due to strain differences in DUOX2 activity.
authors.affiliation: Department of Radiation Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: R Steven
authors.initials: RS
authors.lastname: Esworthy
authors.forename: Byung-Wook
authors.initials: BW
authors.lastname: Kim
authors.forename: Guillermo E
authors.initials: GE
authors.lastname: Rivas
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Leto
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Fong-Fong
authors.initials: FF
authors.lastname: Chu
mesh_terms: D000818:Animals; D002432:Cecum / Q000382:microbiology / Q000473:pathology; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D003092:Colitis / Q000201:enzymology* / Q000235:genetics*; D003106:Colon / Q000473:pathology; D004926:Escherichia coli / Q000254:growth & development; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D012333:RNA, Messenger; D022661:RNA, Untranslated; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1