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Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease

Genes & Immunity volume 11, pages 219–231 (2010)Cite this article

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Abstract

Inflammatory bowel disease (IBD) is a chronic debilitating disease resulting from a complex interaction of multiple genetic factors with the environment. To identify modifier genes of IBD, we used an F2 intercross of IBD-resistant C57BL/6J-Il10−/− mice and IBD-susceptible C3H/HeJBir-Il10−/− (C3Bir-Il10−/−) mice. We found a prominent involvement of lymphatic vessels in IBD and applied a scoring system to quantify lymphatic vascular changes. Quantitative trait locus (QTL) analyses revealed a large-effect QTL on chromosome 3, mapping to an interval of 43.6 Mbp. This candidate interval was narrowed by fine mapping to 22 Mbp, and candidate genes were analyzed by a systems genetics approach that included quantitative gene expression profiling, search for functional polymorphisms, and haplotype block analysis. We identified vascular adhesion molecule 1 (Vcam1) as a candidate modifier gene in the interleukin 10-deficient mouse model of IBD. Importantly, VCAM1 protein levels were increased in susceptible C3H/HeJ mice, compared with C57BL/6J mice; systemic blockade of VCAM1 in C3Bir-Il10−/− mice reduced their inflammatory lymphatic vessel changes. These results indicate that genetically determined expression differences of VCAM1 are associated with susceptibility to colon inflammation, which is accompanied by extensive lymphatic vessel changes. VCAM1 is, therefore, a promising therapeutic target for IBD.

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Acknowledgements

We thank C Halin for scientific advice and G Churchill for inputs on QTL analysis. We thank J Scholl and L Nguyen for technical assistance and B Snijder for assistance with data analysis. This work was supported by National Institutes of Health grant CA69184, Swiss National Science Fund grant 3100A0-108207, Austrian Science Foundation grant S9408-B11, Cancer League Zurich, Oncosuisse and The European Commission grant LSHC-CT-2005-518178 (MD), National Institutes of Health grant DK44240, and Broad Biomedical Research Program (EHL and JPS).

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Authors and Affiliations

  1. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland

    G Jurisic & M Detmar

  2. The Jackson Laboratory, Bar Harbor, ME, USA

    J P Sundberg, E H Leiter & L Alley

  3. Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany

    A Bleich & G Buechler

  4. Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA

    K W Broman

  5. Max Planck Institute of Molecular Biomedicine, Münster, Germany

    D Vestweber

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Jurisic, G., Sundberg, J., Bleich, A. et al. Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease. Genes Immun 11, 219–231 (2010). https://doi.org/10.1038/gene.2010.4

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