Abstract
Inflammatory bowel diseases (IBDs) are complex disorders caused by a combination of environmental, microbial, and genetic factors. Genome-wide association studies in humans have successfully identified multiple genes and loci associated with disease susceptibility, but the mechanisms by which these loci interact with each other and/or with environmental factors (i.e., intestinal microbiota) to cause disease are poorly understood. Helicobacter hepaticus-induced intestinal inflammation in mice is an ideal model system for elucidating the genetic basis of IBD susceptibility in a bacterially induced system, as there are significant differences in H. hepaticus-induced disease susceptibility among inbred mouse strains. Infected A/J mice develop acute overexpression of proinflammatory cytokines followed 2–3 months later by chronic cecal inflammation, whereas infected C57BL/6 mice fail to develop cecal inflammation or increased cytokine expression. The goal of this project was to use quantitative trait locus (QTL) mapping to evaluate genetic factors that contribute to the differential disease susceptibility between these two mouse strains. Using acute cecal IL-12/23p40 expression as a biomarker for disease susceptibility, QTL analysis of H. hepaticus-infected F2 mice revealed involvement of multiple loci. The loci with the strongest association were located on Chromosome 3 and Chromosome 17, with logarithm of odds (LOD) scores of 6.89 and 3.09, respectively. Cecal expression of IL-12/23p40 in H. hepaticus-infected C57BL/6J-Chr3A/J/NaJ chromosome substitution mice had an intermediate phenotype, significantly higher than in resistant C57BL/6 but lower than in susceptible A/J mice, confirming the importance of this locus to the immune response to H. hepaticus infection.
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Acknowledgments
We thank Dr. Stephanie McKay of the Division of Animal Sciences, University of Missouri, for her assistance with the Illumina genotyping platform, and members of the Research Animal Diagnostic Laboratory for their assistance with this project. We also thank Dr. Aaron Ericsson of the Research Animal Diagnostic Laboratory for his assistance in preparing the manuscript. This work was supported by NIH grant K26 RR018811, a grant from the University of Missouri, Department of Veterinary Pathobiology and Research Animal Diagnostic Laboratory research funds.
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Hillhouse, A.E., Myles, M.H., Taylor, J.F. et al. Quantitative trait loci in a bacterially induced model of inflammatory bowel disease. Mamm Genome 22, 544–555 (2011). https://doi.org/10.1007/s00335-011-9343-5
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DOI: https://doi.org/10.1007/s00335-011-9343-5