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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   g lutathione peroxidase-deficiency- a ssociated  c olitis 1  ( Gdac1 ). The aim of this study was to identify the best gene candidates within the  Gdac1  locus contributing to the murine colitis phenotype.    Method/Principal Findings  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.    Conclusion/Significance  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.

Analysis of Candidate Colitis Genes in the Gdac1 Locus of Mice Deficient in Glutathione Peroxidase-1 and -2