title: NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease.
abstract: BACKGROUND
  NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD).
  
  
  METHODS
  Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays.
  
  
  RESULTS
  The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 × 10(-5)). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 × 10(-4)) and late (>8 weeks) leukocytopenia (P = 4.3 × 10(-4)). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001).
  
  
  CONCLUSIONS
  These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Asada
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shioya
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Imaeda
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Inatomi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Bamba
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kito
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan.
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan. andoh@belle.shiga-med.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
mesh_terms: D000328:Adult; D000505:Alopecia / Q000139:chemically induced / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006150:Guanine Nucleotides / Q000097:blood* / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D007958:Leukocyte Count; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D011755:Pyrophosphatases / Q000235:genetics*; D013873:Thionucleotides / Q000097:blood* / Q000502:physiology; D000096964:Nudix Hydrolases
chemical_list: D006150:Guanine Nucleotides; D015122:Mercaptopurine; D011755:Pyrophosphatases; D013873:Thionucleotides; C003964:6-thioguanylic acid; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases
keywords: 6-Mercaptopurine; Azathioprine; IBD; NUDT15