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Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Editorial Board: Benjeddou, Mongi / Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.

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2363-8915
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Volume 33, Issue 1

Issues

Preemptive NUDT15 genotyping: redefining the management of patients with thiopurine-induced toxicity

Swarup A.V. ShahORCID iD: http://orcid.org/0000-0003-1703-5990 / Minal U. Paradkar
  • Research Laboratories, P.D. Hinduja National Hospital and Medical Research Centre, V.S. Marg, Mahim, Mumbai, India
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Devendra C. Desai
  • Department of Gastroenterology, P.D. Hinduja National Hospital and Medical Research Centre, V.S. Marg, Mahim, Mumbai, India
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tester F. Ashavaid
  • Corresponding author
  • Consultant Biochemist, Head – Department of Laboratory Medicine, Director – Lab Research, Department of Biochemistry, P.D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai 400-016, India, Phone: +91 022 24447935, Fax: +91 022 24442318, E-mail:
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2018-02-22 | DOI: https://doi.org/10.1515/dmpt-2017-0038

Abstract

Background:

Thiopurine methyltransferase (TPMT) gene variants have achieved limited success in predicting the outcome of thiopurine therapy, which shows wide inter-individual variations. The literature indicates a strong association between the NUDT15 gene variant and thiopurine-induced toxicity in Asian patients. The present study intends to explore the role of the NUDT15 variant (C415T) in Indian patients on thiopurine therapy.

Methods:

NUDT15 and TPMT genotyping were performed using amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) and the restriction fragment length polymorphism (RFLP) technique.

Results:

Of 370 samples received for TPMT testing, 206 samples were available for NUDT15 genotyping. The NUDT15 risk allele frequency was 10.7%, with the frequency of wild, heterozygous and mutant genotypes being 80.6%, 17.5% and 1.9%, respectively. TPMT variants were seen in 13 of 370 (3.5%) patients, whereas the NUDT15 variant was seen in 40 of 206 (19.4%) patients. Thiopurine-induced toxicity information was available for 101 patients, among whom 10 developed leukopenia and all harbored the NUDT15 variant (p<0.0001). NUDT15 was clinically more relevant than TPMT in terms of sensitivity and specificity, as well as with a statistically significant difference in thiopurine dose requirement for patients with the NUDT15 variant.

Conclusions:

A preemptive NUDT15 genotyping approach can therefore help identify high-risk patients (NUDT15 C415T positive) who could benefit from thiopurine dose reduction, thereby preventing fatal thiopurine-induced toxicity.

Keywords: Indians; NUDT15; preemptive genotyping; thiopurine toxicity; TPMT

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About the article

Received: 2017-11-22

Accepted: 2018-01-23

Published Online: 2018-02-22

Published in Print: 2018-03-28


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: National Health Education Society of P.D. Hinduja National Hospital and Medical Research Centre.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interest: All authors have no conflict of interest to declare. The funding organization played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Drug Metabolism and Personalized Therapy, Volume 33, Issue 1, Pages 57–60, ISSN (Online) 2363-8915, ISSN (Print) 2363-8907, DOI: https://doi.org/10.1515/dmpt-2017-0038.

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