4.8 Article

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

Journal

NATURE GENETICS
Volume 46, Issue 9, Pages 1017-+

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3060

Keywords

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Funding

  1. Biomedical Research Council, the Agency for Science, Technology and Research (A*STAR
  2. BMRC) Singapore [SPF2014/001]
  3. US National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [P01DK046763, U01DK062413, U01AI067068, R01HS021747]
  4. European Union (IBD-BIOM) [305479]
  5. Leona M. and Harry B. Helmsley Charitable Trust [2011PG-MED004, 2014PG-IBD014]
  6. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
  7. NRF (National Research Foundation of Korea) - Ministry of Science, Information and Communication Technology (ICT) and Future Planning [2010-0015648, 2014R1A2A1A09005824]
  8. Korean Health Technology R&D Project from the Ministry of Health and Welfare, the Republic of Korea [A120176]
  9. National Research Foundation of Korea [2014R1A2A1A09005824, 2010-0015648] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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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; P-combined = 4.88 x 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 x 10(-4)). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.

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