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Association of NUDT15 c.415C>T allele and thiopurine-induced leukocytopenia in Asians: a systematic review and meta-analysis

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Abstract

Background

Thiopurines, commonly used to treat autoimmune conditions and cancer, can be limited by life-threatening leucopenia. However, whether NUDT15 (nucleoside diphosphate-linked moiety X-type motif 15) is associated with thiopurine-induced leucopenia in Asians is controversial.

Methods

Relevant studies in English that were published until July 10, 2016 were identified through PubMed, EMbase, and other web knowledge databases. Study quality was assessed according to the Newcastle-Ottawa Scale (NOS) criteria. Summary risk ratio (RR) and 95% confidence intervals (CI) were estimated based on a fixed-effects model or a random-effects model, depending on the absence or presence of significant heterogeneity.

Results

Seven studies of 1138 patients met our inclusion criteria. Random-effects model meta-analysis provided evidence that T carriers of NUDT15 c.415C>T were significantly correlated with high incidences of thiopurine-induced leukocytopenia [CT + TT vs. CC: RR = 3.79, 95%CI (2.64 ~ 5.44), P < 0.00001]. This correlation was especially strong in TT patients, where it was found to be significantly increased by 6.54-fold compared with CC patients [TT vs. CC: RR = 6.54, 95%CI (3.34 ~ 12.82), P < 0.00001]. We also found that the NUDT15 c.415C>T variant was common in Asians and Hispanics, but rare in Europeans and Africans; the frequency of the NUDT15 c.415C>T distribution varied substantially by race/ethnicity.

Conclusion

The results of this meta-analysis confirm that NUDT15 c.415C>T may be an important predictor of thiopurine-induced leukocytopenia in Asians. Genotype targeting of NUDT15 c.415C>T before initiating thiopurine treatment may be useful to limit leukocytopenia.

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References

  1. Anstey A, Lear JT (1998) Azathioprine: clinical pharmacology and current indications in autoimmune disorders. BioDrugs 9:33–47

    Article  CAS  PubMed  Google Scholar 

  2. Lennard L, Van Loon JA, Weinshilboum RM (1989) Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46:149–154

    Article  CAS  PubMed  Google Scholar 

  3. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM (1991) Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119:985–989

    Article  CAS  PubMed  Google Scholar 

  4. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225–229

    Article  CAS  PubMed  Google Scholar 

  5. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM (1987) Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 41:18–25

    Article  CAS  PubMed  Google Scholar 

  6. Relling MV, Gardner EE, Sandborn WJ et al (2013) Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 93:324–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Roberts RL, Barclay ML (2015) Update on thiopurine pharmacogenetics in inflammatory bowel disease. Pharmacogenomics 16:891–903

    Article  CAS  PubMed  Google Scholar 

  8. McLeod HL, Pritchard SC, Githang'a J et al (1999) Ethnic differences in thiopurine methyltransferase pharmacogenetics: evidence for allele specificity in Caucasian and Kenyan individuals. Pharmacogenetics 9:773–776

    Article  CAS  PubMed  Google Scholar 

  9. Collie-Duguid ES, Pritchard SC, Powrie RH et al (1999) The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 9:37–42

    Article  CAS  PubMed  Google Scholar 

  10. Kim JH, Cheon JH, Hong SS et al (2010) Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J Clin Gastroenterol 44:e242–e248

    Article  CAS  PubMed  Google Scholar 

  11. Tajiri H, Tomomasa T, Yoden A et al (2008) Efficacy and safety of azathioprine and 6-mercaptopurine in Japanese pediatric patients with ulcerative colitis: a survey of the Japanese Society for Pediatric Inflammatory Bowel Disease. Digestion 77:150–154

    Article  CAS  PubMed  Google Scholar 

  12. Takatsu N, Matsui T, Murakami Y et al (2009) Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 24:1258–1264

    Article  CAS  PubMed  Google Scholar 

  13. Asada A, Nishida A, Shioya M et al (2016) NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol 51:22–29

    Article  CAS  PubMed  Google Scholar 

  14. Lee YJ, Hwang EH, Park JH et al (2016) NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn’s disease. Eur J Gastroenterol Hepatol. doi:10.1097/MEG.0000000000000564

    Google Scholar 

  15. Liang DC, Yang CP, Liu HC et al (2015) NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J 16:536–539

    Article  PubMed  Google Scholar 

  16. N. NCI (2009) National Cancer Institute, common terminology criteria for adverse events v4. NIH publication, Bethesda 09-7473

    Google Scholar 

  17. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605

    Article  PubMed  Google Scholar 

  18. Zintzaras E, Ioannidis JP (2005) HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics 21:3672–3673

    Article  CAS  PubMed  Google Scholar 

  19. Peters JL, Sutton AJ, Jones DR et al (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295:676–680

    Article  CAS  PubMed  Google Scholar 

  20. Chiengthong K, Ittiwut C, Muensri S et al (2016) NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica 101:e24–e26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kakuta Y, Naito T, Onodera M et al (2015) NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J 16:280–285

    Article  PubMed  Google Scholar 

  22. Tanaka Y, Kato M, Hasegawa D et al (2015) Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol 171:109–115

    Article  CAS  PubMed  Google Scholar 

  23. Yang SK, Hong M, Baek J et al (2014) A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46:1017–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhu X, Chao K, Wang X et al (2016) NUDT15 R139C genotype is a determinant of thiopurines-induced leukopenia in Chinese patients with Crohn’s disease. Gastroenterology 150:S318

    Article  Google Scholar 

  25. Shah SA, Paradkar M, Desai D et al (2016) Nudt15 C415t variant as a predictor for thiopurine induced toxicity in Indian patients. J Gastroenterol Hepatol. doi:10.1111/jgh.13494

    Google Scholar 

  26. Suzuki H, Fukushima H, Suzuki R et al (2016) Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age. J Hum Genet 61:797–801

    Article  CAS  PubMed  Google Scholar 

  27. Yang JJ, Landier W, Yang W et al (2015) Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 33:1235–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meijer B, Mulder CJ, de Boer NK (2016) NUDT15: a novel player in thiopurine metabolism. J Gastrointestin Liver Dis 25:261–262

    PubMed  Google Scholar 

  29. Ebbesen MS, Nersting J, Jacobsen JH et al (2013) Incorporation of 6-thioguanine nucleotides into DNA during maintenance therapy of childhood acute lymphoblastic leukemiaThe influence of thiopurine methyltransferase genotypes. J Clin Pharmacol 53:670–674

    Article  CAS  PubMed  Google Scholar 

  30. Fotoohi AK, Coulthard SA, Albertioni F (2010) Thiopurines: factors influencing toxicity and response. Biochem Pharmacol 79:1211–1220

    Article  CAS  PubMed  Google Scholar 

  31. Hedeland RL, Hvidt K, Nersting J et al (2010) DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Cancer Chemother Pharmacol 66:485–491

    Article  CAS  PubMed  Google Scholar 

  32. Takagi Y, Setoyama D, Ito R et al (2012) Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem 287:21541–21549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moriyama T, Nishii R, Perez-Andreu V et al (2016) NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 48:367–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe Road, Erqi District, 450052, Zhengzhou, People’s Republic of China

    A. L. Zhang, J. Yang, H. Wang, J. L. Lu, S. Tang & X. J. Zhang

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  1. A. L. Zhang
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  2. J. Yang
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  3. H. Wang
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  4. J. L. Lu
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Correspondence to X. J. Zhang.

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The authors declare that they have no conflict of interest.

Source of funding

This study was funded by the Science and Technology Planning Project of Henan Province, China (grant number 201601001).

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Zhang, A.L., Yang, J., Wang, H. et al. Association of NUDT15 c.415C>T allele and thiopurine-induced leukocytopenia in Asians: a systematic review and meta-analysis. Ir J Med Sci 187, 145–153 (2018). https://doi.org/10.1007/s11845-017-1608-x

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  • DOI: https://doi.org/10.1007/s11845-017-1608-x

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