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NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease

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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.

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Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K08967), a grant for the Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan, a grant from the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and development, AMED, and a grant from Smoking Research Foundation.

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Authors and Affiliations

  1. Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, 520-2192, Japan

    Ayumi Asada, Atsushi Nishida, Makoto Shioya, Hirotsugu Imaeda, Osamu Inatomi, Shigeki Bamba, Katsuyuki Kito, Mitsushige Sugimoto & Akira Andoh

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  1. Ayumi Asada
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  2. Atsushi Nishida
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Correspondence to Akira Andoh.

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The authors, except Akira Andoh, disclose no conflict of interest. Akira Andoh reports speaker fees from AbbVie and Eisai Pharmaceutical.

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Updates

This article was updated on December 1, 2015. Two values were corrected in Table 3 (−4.550 should be −4550 and −4.430 should be −4430).

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Asada, A., Nishida, A., Shioya, M. et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol 51, 22–29 (2016). https://doi.org/10.1007/s00535-015-1142-4

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