NUDT15 R139C is a specific but insensitive pre-treatment screen for thiopurine-induced leukopenia: a meta-analysis of eight cohorts from six countries.

Background: Loss-of-function variation in NUDT15 causes thiopurine-induced leukopenia, and genotype-based dosing recommendations exist. Earlier syntheses pooled East Asian cohorts almost exclusively, and the performance of the variant as a screening test in other populations has not been examined. Methodology: A curated set of full-text studies on NUDT15 and thiopurine toxicity held by the authors was analysed, checked against a PubMed and Google Scholar search to July 2026. Studies reporting leukopenia by NUDT15 c.415C>T (rs116855232) genotype in azathioprine- or mercaptopurine-treated patients were eligible. Two-by-two tables were pooled by DerSimonian–Laird random-effects meta-analysis, with accuracy and absolute-risk analyses restricted by study design. Certainty was rated by GRADE. The analysis was not registered, and the search was not exhaustive. Results: Eight studies (1 702 patients, 355 events) from six countries were included. Carriage was associated with leukopenia (pooled odds ratio 5.70, 95% CI 3.44–9.45; prediction interval 1.48–21.99; moderate certainty) and raised absolute risk by 38.7 percentage points (95% CI 28.2–49.1). Excluding the exposure-matched cohort, pooled sensitivity was 40.3% (95% CI 29.9–51.6) and specificity 89.9% (95% CI 85.6–93.1). Sensitivity was 49.5% in East and Southeast Asian cohorts and 28.0% in Indian cohorts (p=0.009; very low certainty). The number genotyped per excess episode was 12 in East and Southeast Asian populations, 23 in South Asian populations, and about 774 in European populations. Conclusion: The association holds outside East Asia, but the variant is a rule-in rather than a rule-out marker: a normal R139C result should not be read as permission to relax haematological monitoring. The lower sensitivity in Indian cohorts is hypothesis-generating. Recommendation: Prospective multi-ancestry cohorts genotyping a full NUDT15 panel alongside TPMT, with a common leukopenia definition, are needed before an ancestry-specific testing policy is set.