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Genetic Testing in Crohn Disease

Utility in Individualizing Patient Management

  • Practical Pharmacogenomics
  • Published:
American Journal of Pharmacogenomics

Abstract

Inflammatory bowel disease (IBD), with its two subforms of Crohn disease and ulcerative colitis, is a polygenic disease that manifests due to environmental trigger factors on the background of a complex genetic predisposition. The first risk gene underlying susceptibility to Crohn disease has been identified as CARD15 (located on chromosome 16q12, encoding NOD2). Three single nucleotide polymorphisms in the leucine rich region (LRR) of this gene are strongly and independently associated with Crohn disease susceptibility and explain up to 20% of the total genetic predisposition for Crohn disease. These variants have been consistently replicated as associated with a particular sub-phenotype characterized by small bowel (ileum) involvement and early age at onset. Presently, genetic testing for the CARD15 variants has only a modest relevance in clinical practice.

The most attractive use of genetic testing is for the prediction of response to therapy. Most therapies only show efficacy in subgroups of patients and no clinical parameters are available to distinguish, prior to therapy, whether the patients will be responders or non-responders, or if the patients will experience adverse effects. The pharmacogenetic basis of toxicity is well known for azathioprine: several thiopurine methyltransferase (TPMT) polymorphisms that are associated with reduced activity of this thiopurine drug metabolizing enzyme result in cytotoxic and immunosuppressive adverse effects of azathioprine. Genetic screening, which has found its way into routine clinical diagnostics, allows the identification of the patients who will not tolerate a standard dose of the drug. The extensive search for genetic predictors of response to the anti-tumor necrosis factor treatment with infliximab, which results in a remission rate of 30–40%, has, however, failed to indentify a variation associated with a differential response.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgments

This work was supported by grants from the European Commission (Genomics of IBD), the Competence Network Inflammatory Bowel Disease (www.kompetenznetz-ced.de), and the German National Genome Research Network (www.ngfn.de). ## Some of the own pharmacogenetic studies of the therapy with infliximab in Crohn disease that are referenced were funded in part by a grant from Centocor. ## Stefan Schreiber served as a consultant for Centocor/Schering Plough and, as an invited speaker, received honoraria from various companies.

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  1. Institute for Clinical Molecular Biology, Christian-Albrechts-Universtität Kiel, Schittenhelmstr. 12, Kiel, D-24105, Germany

    Silvia Mascheretti &  Stefan Schreiber

  2. Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany

    Silvia Mascheretti &  Stefan Schreiber

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  1. Silvia Mascheretti
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Correspondence to Stefan Schreiber.

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Mascheretti, S., Schreiber, S. Genetic Testing in Crohn Disease. Am J Pharmacogenomics 5, 213–222 (2005). https://doi.org/10.2165/00129785-200505040-00002

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