Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Shintaro Akiyama, Katsuyoshi Matsuoka, Kyoko Fukuda, Shunsuke Hamada, Mikiko Shimizu, Kosaku Nanki, Shinta Mizuno, Hiroki Kiyohara, Mari Arai, Shinya Sugimoto, Yasushi Iwao, Haruhiko Ogata, Tadakazu Hisamatsu, Makoto Naganuma, Maiko Motobayashi, Kohei Suzuki, Kento Takenaka, Toshimitsu Fujii, Eiko Saito, Masakazu NagahoriKazuo Ohtsuka, Mayumi Mochizuki, Mamoru Watanabe, Masayuki Hashiguchi, Takanori Kanai

Research output: Contribution to journalReview article

Abstract

Background and Aim: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Original languageEnglish
JournalJournal of Gastroenterology and Hepatology (Australia)
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Inflammatory Bowel Diseases
Erythrocyte Indices
Leukopenia
Leukocyte Count
Genotype
Diphosphates
Platelet Count
Ulcerative Colitis
Nucleosides
Crohn Disease
Tumor Necrosis Factor-alpha
Polymerase Chain Reaction
Genes

Keywords

  • inflammatory bowel disease
  • leukopenia
  • long-term thiopurine administration
  • mean corpuscular volume
  • NUDT15

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine. / Akiyama, Shintaro; Matsuoka, Katsuyoshi; Fukuda, Kyoko; Hamada, Shunsuke; Shimizu, Mikiko; Nanki, Kosaku; Mizuno, Shinta; Kiyohara, Hiroki; Arai, Mari; Sugimoto, Shinya; Iwao, Yasushi; Ogata, Haruhiko; Hisamatsu, Tadakazu; Naganuma, Makoto; Motobayashi, Maiko; Suzuki, Kohei; Takenaka, Kento; Fujii, Toshimitsu; Saito, Eiko; Nagahori, Masakazu; Ohtsuka, Kazuo; Mochizuki, Mayumi; Watanabe, Mamoru; Hashiguchi, Masayuki; Kanai, Takanori.

In: Journal of Gastroenterology and Hepatology (Australia), 01.01.2019.

Research output: Contribution to journalReview article

Akiyama, S, Matsuoka, K, Fukuda, K, Hamada, S, Shimizu, M, Nanki, K, Mizuno, S, Kiyohara, H, Arai, M, Sugimoto, S, Iwao, Y, Ogata, H, Hisamatsu, T, Naganuma, M, Motobayashi, M, Suzuki, K, Takenaka, K, Fujii, T, Saito, E, Nagahori, M, Ohtsuka, K, Mochizuki, M, Watanabe, M, Hashiguchi, M & Kanai, T 2019, 'Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine', Journal of Gastroenterology and Hepatology (Australia). https://doi.org/10.1111/jgh.14693
Akiyama, Shintaro ; Matsuoka, Katsuyoshi ; Fukuda, Kyoko ; Hamada, Shunsuke ; Shimizu, Mikiko ; Nanki, Kosaku ; Mizuno, Shinta ; Kiyohara, Hiroki ; Arai, Mari ; Sugimoto, Shinya ; Iwao, Yasushi ; Ogata, Haruhiko ; Hisamatsu, Tadakazu ; Naganuma, Makoto ; Motobayashi, Maiko ; Suzuki, Kohei ; Takenaka, Kento ; Fujii, Toshimitsu ; Saito, Eiko ; Nagahori, Masakazu ; Ohtsuka, Kazuo ; Mochizuki, Mayumi ; Watanabe, Mamoru ; Hashiguchi, Masayuki ; Kanai, Takanori. / Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine. In: Journal of Gastroenterology and Hepatology (Australia). 2019.
@article{afca3e0be9b14dc1b518025a90d20bf6,
title = "Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine",
abstract = "Background and Aim: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results: The included patients had either Crohn's disease (54; 65.1{\%}) or ulcerative colitis (29; 34.9{\%}). Genotyping of NUDT15 R139C identified 62 patients (74.7{\%}) of genotype C/C and 21 (25.3{\%}) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.",
keywords = "inflammatory bowel disease, leukopenia, long-term thiopurine administration, mean corpuscular volume, NUDT15",
author = "Shintaro Akiyama and Katsuyoshi Matsuoka and Kyoko Fukuda and Shunsuke Hamada and Mikiko Shimizu and Kosaku Nanki and Shinta Mizuno and Hiroki Kiyohara and Mari Arai and Shinya Sugimoto and Yasushi Iwao and Haruhiko Ogata and Tadakazu Hisamatsu and Makoto Naganuma and Maiko Motobayashi and Kohei Suzuki and Kento Takenaka and Toshimitsu Fujii and Eiko Saito and Masakazu Nagahori and Kazuo Ohtsuka and Mayumi Mochizuki and Mamoru Watanabe and Masayuki Hashiguchi and Takanori Kanai",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/jgh.14693",
language = "English",
journal = "Journal of Gastroenterology and Hepatology (Australia)",
issn = "0815-9319",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

AU - Akiyama, Shintaro

AU - Matsuoka, Katsuyoshi

AU - Fukuda, Kyoko

AU - Hamada, Shunsuke

AU - Shimizu, Mikiko

AU - Nanki, Kosaku

AU - Mizuno, Shinta

AU - Kiyohara, Hiroki

AU - Arai, Mari

AU - Sugimoto, Shinya

AU - Iwao, Yasushi

AU - Ogata, Haruhiko

AU - Hisamatsu, Tadakazu

AU - Naganuma, Makoto

AU - Motobayashi, Maiko

AU - Suzuki, Kohei

AU - Takenaka, Kento

AU - Fujii, Toshimitsu

AU - Saito, Eiko

AU - Nagahori, Masakazu

AU - Ohtsuka, Kazuo

AU - Mochizuki, Mayumi

AU - Watanabe, Mamoru

AU - Hashiguchi, Masayuki

AU - Kanai, Takanori

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background and Aim: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

AB - Background and Aim: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

KW - inflammatory bowel disease

KW - leukopenia

KW - long-term thiopurine administration

KW - mean corpuscular volume

KW - NUDT15

UR - http://www.scopus.com/inward/record.url?scp=85068268713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068268713&partnerID=8YFLogxK

U2 - 10.1111/jgh.14693

DO - 10.1111/jgh.14693

M3 - Review article

C2 - 31045285

AN - SCOPUS:85068268713

JO - Journal of Gastroenterology and Hepatology (Australia)

JF - Journal of Gastroenterology and Hepatology (Australia)

SN - 0815-9319

ER -