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Nat Genet. 2014 Sep;46(9):1017-20. doi: 10.1038/ng.3060. Epub 2014 Aug 10.

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

Author information

1
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
2
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
3
Human Genetics Group, Genome Institute of Singapore, Singapore.
4
The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
5
Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
6
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

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; P(combined) = 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.

PMID:
25108385
PMCID:
PMC4999337
DOI:
10.1038/ng.3060
[Indexed for MEDLINE]
Free PMC Article
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