Letter | Published:

A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia

Nature Genetics volume 46, pages 10171020 (2014) | Download Citation

Abstract

Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; Pcombined = 4.88 × 10−94). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10−4). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.

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Acknowledgements

We would like to thank all participants who provided the DNA and clinical information necessary for this study. J.L. and W.Z. are supported by the Biomedical Research Council, the Agency for Science, Technology and Research (A*STAR; BMRC SPF2014/001), Singapore. D.P.B.M., T.H. and M.D. are supported by the US National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (P01DK046763, U01DK062413, U01AI067068, R01HS021747), the European Union (IBD-BIOM 305479), the Leona M. and Harry B. Helmsley Charitable Trust (2011PG-MED004, 2014PG-IBD014) and internal funding from the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute. This work was supported by a Mid-Career Researcher Program grant through NRF (National Research Foundation of Korea) to K.S. (2010-0015648, 2014R1A2A1A09005824) funded by the Ministry of Science, Information and Communication Technology (ICT) and Future Planning and by a Korean Health Technology R&D Project grant to S.-K.Y. (A120176) from the Ministry of Health and Welfare, the Republic of Korea.

Author information

Affiliations

  1. Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

    • Suk-Kyun Yang
    • , Byong Duk Ye
    • , Kyung-Jo Kim
    • , Sang Hyoung Park
    • , Soo-Kyung Park
    •  & Dong-Hoon Yang
  2. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.

    • Myunghee Hong
    • , Jiwon Baek
    • , Hyunchul Choi
    • , Yusun Jung
    •  & Kyuyoung Song
  3. Human Genetics Group, Genome Institute of Singapore, Singapore.

    • Wanting Zhao
    •  & Jianjun Liu
  4. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Talin Haritunians
    •  & Dermot P B McGovern
  5. Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Marla Dubinsky
  6. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

    • Inchul Lee

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Contributions

K.S. and S.-K.Y. obtained financial support and conceived and designed the study. K.S. supervised genotyping, data analysis and interpretation, and S.-K.Y. supervised all the sample collection, data analysis and interpretation. J.L. supervised data analysis and interpretation. S.-K.Y., B.D.Y., K.-J.K., S.H.P., S.-K.P., D.-H.Y. and I.L. recruited subjects and participated in diagnostic evaluation. S.-K.Y., S.H.P. and S.-K.P. assessed clinical features. T.H., M.D. and D.P.B.M. supervised the Immunochip genotyping and provided their data. M.H., W.Z., Y.J. and H.C. performed data analyses. M.H., J.B. and H.C. prepared DNA samples and performed genotyping. J.B. performed in vitro transfection experiments and data analysis. K.S. and S.-K.Y. drafted the manuscript. K.S., S.-K.Y., D.P.B.M. and J.L. revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kyuyoung Song.

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DOI

https://doi.org/10.1038/ng.3060

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