Time to incorporate preemptive NUDT15 testing before starting thiopurines in inflammatory bowel disease in Asia and beyond: a review

ABSTRACT

Introduction

Thiopurine toxicity is related to genetic polymorphism. Thiopurine methyltransferase (TPMT) variants do not explain thiopurine toxicity in more than half of patients. Asians, despite the low prevalence of TPMT variants, are more susceptible to thiopurine toxicity. Since 2014, studies from many Asian countries have shown a strong association between nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 polymorphism and thiopurine-induced myelotoxicity.

Areas covered

An English language literature search was performed for TPMT and NUDT15 genetic variants in inflammatory bowel disease and other diseases. This article discusses the merits of preemptive NUDT15 and TPMT testing in Asian and non-Asian IBD populations.

Expert opinion

The NUDT polymorphism occurs in up to 27% of the Asian and Hispanic population. Hematological toxicity occurs in up to one-third of patients with this genetic variant. Given this, preemptive testing for NUDT15 variant is worthwhile and is probably more cost-effective than TPMT testing in these groups. Prevalence of NUDT15 variants is low in non-Finnish European population, but NUDT15 variants have been linked to myelotoxicity along with TPMT genetic variants. NUDT15 preemptive testing should be considered in the migrant Asian population in Europe and North America and in Caucasian populations who develop myelotoxicity.

Plain Language Summary

The treatment of patients with inflammatory bowel diseases (ulcerative colitis andCrohn’s disease) is based on the severity of the disease. They may need drugs called ‘thiopurines’ if the disease is not controlled by initial therapy. These drugs have side effects which are related to genetic variations. These side effects can be potentially prevented by testing for these genetic variants prior to starting these drugs. These tests include thiopurine methyltransferase (TPMT) genotype testing and nucleoside diphosphate-linked moiety X-typemotif (NUDT) 15 genotype testing. By doing these tests before starting the drugs, the dose can be modified to prevent side effects on the bone marrow and other tissues.

KEYWORDS:

• Inflammatory bowel disease
• thiopurines
• thiopurine metabolism
• thiopurine toxicity
• thiopurine toxicity in Asian
• ulcerative colitis
• Crohn’s disease

Article highlights

• Thiopurines remain an important tool in the therapy armamentarium of inflammatory bowel diseases, but drug withdrawal is often required due to toxicity, especially myelotoxicity.

• Genetic variants in thiopurine methyl transferase (TPMT) enzyme explain thiopurine toxicity in some patients, but TPMT variants are uncommon in Asian people.

• Nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 polymorphism was described in 2014 and is more common in Asian and Hispanic populations as compared to the Western population. It explains most of the genetic susceptibility of Asians to thiopurine toxicity.

• Pre-emptive NUDT15 variant testing has the potential to mitigate thiopurine toxicity. It should be considered in Asian and Hispanic populations as well as migrant Asians and people in Europe and North America who developing myelotoxicity on thiopurine therapy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Acknowledgments

The authors would like to gratefully acknowledge Dr Swarup Shah for his help in review of the manuscript.

Additional information

Funding

This paper was not funded.