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.

• Authors: 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 Nagahori, Kazuo Ohtsuka, Mayumi Mochizuki, Mamoru Watanabe, Masayuki Hashiguchi, Takanori Kanai
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 34 Issue 10 Pg. 1751-1757 (Oct 2019) ISSN: 1440-1746 [Electronic] Australia
• PMID: 31045285 (Publication Type: Journal Article)
• Copyright: © 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Chemical References

• Anti-Inflammatory Agents
• Gastrointestinal Agents
• Mercaptopurine
• NUDT15 protein, human
• Pyrophosphatases
• Azathioprine

Topics

• Adult
• Anti-Inflammatory Agents (adverse effects)
• Azathioprine (adverse effects)
• Colitis, Ulcerative (diagnosis, drug therapy)
• Crohn Disease (diagnosis, drug therapy)
• Erythrocyte Indices
• Female
• Gastrointestinal Agents (adverse effects)
• Genetic Predisposition to Disease
• Heterozygote
• Humans
• Leukocyte Count
• Leukopenia (blood, chemically induced, diagnosis, genetics)
• Male
• Mercaptopurine (adverse effects)
• Middle Aged
• Mutation, Missense
• Pyrophosphatases (genetics)
• Retrospective Studies
• Risk Factors
• Time Factors
• Tokyo
• Treatment Outcome
• Young Adult