Prevalence of NUDT15 Genetic Variants and Incidence of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Abstract

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: Twenty studies comprising 5232 patients were included. The pooled prevalence of the ∗1/∗3 c.415C>T C/T diplotype was 13% (95% confidence interval [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.