Prevalence of NUDT15 genetic variants and incidence of thiopurine-induced leukopenia in Inflammatory Bowel Disease: A systematic review and meta-analysis

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Authors
Yu, N.
Sriranganathan, D.
Walker, G. J.
Sazonovs, A.
Wilding, H.
Roberts, C.
Kennedy, N. A.
Ahmad, T.
Boyapati, R. K.
Ding, N. S.
Journal
Journal of Crohn's and Colitis
Type
Journal Article
Publisher
Oxford University Press
Rights
© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.
BACKGROUND AND AIMS: Nudix hydrolase 15 (NUDT15) genetic variants confer an increased risk of thiopurine-induced leukopenia (TIL), however their global prevalence in Inflammatory Bowel Disease (IBD) patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients. METHODS: Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants, were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early (≤8 weeks) and late (>8 weeks) leukopenia, and relative risk of developing leukopenia. RESULTS: 20 studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C>T C/T diplotype was 13% (95% CI: 10-18%), *3/*3 c.415C>T T/T diplotype was 2% (95% CI: 1-2%), *1/*5 c.52G>A G/A diplotype was 2% (95% CI: 1-3%) and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% (95% CI: 4-12%). The pooled prevalence of *1/*3 was high in Japanese (20%, 95% CI: 16-24%) and Chinese patients (18%, 95% CI: 12-27%). The incidence of early leukopenia was 20% (95% CI: 16-26%) in *1/*3 patients, 99% (95% CI: 7-100%) in *3/*3 patients and 49% (95% CI: 29-69%) in *1/*6 patients. The incidence of late leukopenia was 36% (95% CI: 26-49%) in *1/*3 patients. CONCLUSIONS: NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations to guide thiopurine dosing and prevent myelotoxicity.
Citation
Yu N, Sriranganathan D, Walker GJ, Sazonovs A, Wilding H, Roberts C, et al. Prevalence of NUDT15 genetic variants and incidence of thiopurine-induced leukopenia in Inflammatory Bowel Disease: A systematic review and meta-analysis. J Crohns Colitis. 2023.
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