title: A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.
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.
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Suk-Kyun
authors.initials: SK
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Myunghee
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Baek
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hyunchul
authors.initials: H
authors.lastname: Choi
authors.affiliation: Human Genetics Group, Genome Institute of Singapore, Singapore.
authors.forename: Wanting
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Yusun
authors.initials: Y
authors.lastname: Jung
authors.affiliation: The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Byong Duk
authors.initials: BD
authors.lastname: Ye
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kyung-Jo
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Sang Hyoung
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Dubinsky
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Inchul
authors.initials: I
authors.lastname: Lee
authors.affiliation: The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Human Genetics Group, Genome Institute of Singapore, Singapore.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kyuyoung
authors.initials: K
authors.lastname: Song
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase
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