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  • Review Article
  • Published:

The role of pharmacogenetics in nonmalignant gastrointestinal diseases

Nature Reviews Gastroenterology & Hepatology volume 9, pages 173–184 (2012)Cite this article

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Abstract

Genetic variation influences the absorption and efflux of drugs in the intestine, the metabolism of drugs in the liver and the effects of these drugs on their target proteins. Indeed, variations in genes whose products have a role in the pathophysiology of nonmalignant gastrointestinal diseases, such as IBD, have been shown to affect the response of patients to therapy. This Review provides an overview of pharmacogenetics in the management of nonmalignant gastrointestinal diseases on the basis of data from clinical trials. Genetic variants that have the greatest effect on the management of patients with IBD involve the metabolism of thiopurines. Variation in drug metabolism by cytochrome P450 enzymes also requires attention so as to avoid drug interactions in patients receiving tricyclic antidepressants and PPIs. Few genotyping tests are currently used in the clinical management of patients with nonmalignant gastrointestinal diseases, owing to a lack of data from clinical trials showing their effectiveness in predicting nonresponse or adverse outcomes. However, pharmacogenetics could have a beneficial role in enabling pharmacotherapy for nonmalignant gastrointestinal diseases to be targeted to the individual patient.

Key Points

  • Genetic variations can affect drug absorption, efflux, metabolism and the ability of drugs to interact with their target proteins

  • Drug interactions might result from concomitant use of medications that alter the function of cytochrome P450 enzymes

  • Activity of the platelet function inhibitor, clopidogrel, is affected by medications (including PPIs) that alter CYP2C19 function; the clinical impact of coadministration of clopidogrel and PPIs, however, is unclear

  • Thiopurine dosage in patients with IBD is typically monitored with blood counts and, if necessary, 6-thioguanine or other metabolite levels, rather than genotyping the thiopurine methyltransferase gene

  • Genotyping is generally not applied in clinical management of nonmalignant gastrointestinal diseases because of the lack of clinical trial evidence that it predicts adverse effects or nonresponse

  • In nonmalignant gastrointestintal diseases, pharmacogenetics might facilitate individualized medicine in the future

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Figure 1: Distribution of CYP2 altered activity variants in different geographic regions.
Figure 2: Overview of thiopurine metabolism.
Figure 3: Structure of SLC6A4.
Figure 4: Hypothetical explanations for the association of alosetron treatment with slow colonic transit in SLC6A4*LL carriers and diarrhea-predominant IBS, and the worse clinical response to tegaserod in patients who are SLC6A4*LL carriers with constipation-predominant IBS.
Figure 5: Genetic variation in proteins involved in bile acid synthesis is associated with colonic transit in patients with IBS.

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Acknowledgements

M. Camilleri is supported in part by research grants from NIH (DK-067071, DK-092179, DK-079866). The nomenclature used throughout this Review follows the HUGO Gene Nomenclature Committee, which has assigned unique gene symbols and names to more than 32,000 human loci, of which over 19,000 are protein coding (http://www.genenames.org/).

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    Michael Camilleri

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Camilleri, M. The role of pharmacogenetics in nonmalignant gastrointestinal diseases. Nat Rev Gastroenterol Hepatol 9, 173–184 (2012). https://doi.org/10.1038/nrgastro.2012.2

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