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Association between the c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms of NUDT 15 and thiopurine-induced leukopenia, thiopurine intolerance, and severe hair loss: an updated meta-analysis

Authors Wang R, Liu B, Li J, Xu J, Wang X, Zhao Z, Zhao L

Received 29 March 2019

Accepted for publication 1 July 2019

Published 5 August 2019 Volume 2019:13 Pages 2729—2744


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo

Ruili Wang,1,2 Baogang Liu,2 Jiapeng Li,1 Jiamin Xu,1 Xiaoling Wang,1 Zhigang Zhao,2 Libo Zhao1

1Clinical Research Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, People’s Republic of China; 2Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China

Purpose: As a common immunosuppressive and anticancer drug, thiopurine has achieved remarkable clinical success. However, higher inter-individual dose variability and unpredictable toxicity still challenge its use in clinical practices. Some studies indicate that NUDT 15 polymorphisms are associated with this variation, but specific correlation remains controversial. This meta-analysis assessed the association between three polymorphisms of NUDT 15 and thiopurine-induced toxicities.
Methods: Three databases were electronically searched: PubMed, Embase, and Web of Science. Only case–control studies and cohort studies were eligible. The overall pooled ORs and corresponding 95% CIs were used to represent the results.
Findings: We included 16 studies that focus on NUDT 15 c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms in patients treated with thiopurine. Significant associations between NUDT 15 c.415C > T polymorphism and leukopenia were found in all genetic models (TC/TT vs CC, OR: 7.64, 95% CI: (6.19, 9.44), P<0.00001; TT vs CC/TC, OR: 29.66, 95% CI: (12.31, 71.46), P<0.00001; TT vs CC, OR: 45.60, 95% CI: (18.84, 110.37), P<0.00001; TC vs CC, OR: 6.41, 95% CI: (5.19, 7.94), P<0.00001; TT vs TC, OR: 6.38, 95% CI: (2.59, 15.72), P<0.00001), early/late leukopenia (in recessive and co-dominant model), leukopenia (grade 3–4), and severe hair loss in all genetic models. Besides, c.52G > A and 36_37insGGAGTC polymorphisms were also significantly associated with leukopenia. No significant association between NUDT 15 c.415C > T polymorphism and early/late leukopenia in the Chinese population was determined in the co-dominant model (TC vs CC).
Implications: NUDT 15 c.415C > T polymorphism could increase the risk of leukopenia, early/late leukopenia, leukopenia (grade 3–4), and severe hair loss. Meanwhile, c.52G > A and c.36_37insGGAGTC mutations also probably increase the risk of leukopenia. Preemptive tests for NUDT 15 polymorphisms are highly recommended to individualize the treatment of thiopurine for a better outcome with less toxicity.

Keywords: NUDT 15, polymorphism, leukopenia, thiopurine, intolerance, meta-analysis

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