Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis. (September 2018)

• Record Type: Journal Article
• Authors: Cargnin, Sarah; Genazzani, Armando A.; Canonico, Pier Luigi; Terrazzino, Salvatore
• Is Part Of: Pharmacological research. Volume 135(2018)
• Page Start: 102
• Page End: 111
• Publication Date: 2018-09
• Subjects: Thiopurines -- Toxicity -- Leukopenia -- NUDT15 -- Polymorphisms; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.07.021
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46–13.03), as compared to rs554405994 (4.336, 95% CI 2.924–6.429) or rs186364861 (2.742, 95% CI 1.453–5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93–1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78–9.20; rs554405994: 2.94, 95% CI 1.74–4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52–4.43; rs554405994: 2.02, 95% CI 0.93–4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.