Identification of novel loci controlling IBD susceptibility utilizing the genetic diversity of wild-derived mice

Abstract

Abstract Inflammatory bowel disease (IBD) is a complex disease that imposes a significant and growing health burden in industrialized nations. Recent genetic studies have identified multiple genetic associations with IBD, but the mechanisms underlying these associations are poorly understood. Animal models are needed to bridge this gap in knowledge, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity and to identify new genetic loci that control susceptibility to IBD, we utilized a panel of chromosome (Chr) substitution (consomic) strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background. Two models of IBD were used, TNBS- and DSS-induced colitis. Multiple disease severity parameters were evaluated, including weight loss, disease activity, fecal Lipocalin-2 production, and histopathology. Strikingly, compared with B6 mice, wild-derived PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we found several PWD-derived loci that exhibited significant effects on IBD susceptibility. Most pronounced was a locus on Chr2, which resulted in very high susceptibility to both DSS and TNBS colitis, while several other PWD-derived loci were protective. Altogether, our experiments identified novel IBD susceptibility loci, harboring genes that control susceptibility to various aspects of IBD pathogenesis, and underscoring the utility of wild-derived mouse genetics. Future studies will identify these genes and their functions, to generate new insights into IBD etiology and pathophysiology.