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Review
. 2019 Jun 7;25(21):2539-2548.
doi: 10.3748/wjg.v25.i21.2539.

Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics

Michiel Dirk Voskuil  1 , Amber Bangma  2 , Rinse Karel Weersma  2 , Eleonora Anna Margaretha Festen  2
Affiliations
Review

Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics

Michiel Dirk Voskuil et al. World J Gastroenterol. .

Abstract

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

Keywords: Crohn’s disease; Inflammatory bowel disease; Personalized medicine; Pharmacogenetics; Ulcerative colitis.

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Conflict of interest statement

Conflict-of-interest statement: R.K.W. received unrestricted research grants from Takeda, Tramedico and Ferring. E.A.M.F. received an unrestricted research grant from Takeda. The remaining authors disclose no conflicts.

Figures

Figure 1
Figure 1
Example of an automated computational pipeline that creates an individual pharmacogenetic passport based on an individual’s genotype. In this case, the individual is a heterozygous carrier of the loss-of-function TPMT*3A allele and homozygous carrier of the NUDT15*1 allele. Heterozygous carriers of TPMT*3A are at risk for thiopurine-induced myelosuppression due to intermediate TPMT enzyme activity levels. Hence, a reduced dose (30%-80% of target dose) is strongly recommended. Patients with a NUDT15*1/*1 genotype are considered as NUDT15 normal metabolizers[28]. TPMT: Thiopurine S-methyltransferase; NUDT: Nudix hydrolase.
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