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.