Background As a common immunosuppressive and anticancer drug, thiopurine can cause life-threatening leukopenia, partly explained by TPMT polymorphism. Recent studies discovered NUDT 15 mutation are associated with thiopurine-induced leukopenia, especially in East Asian, but specific results remain unclear. This system review and meta-analysis was conducted to determine whether the NUDT 15 polymorphism is associated with thiopurine-induced leukopenia and severe hair loss.
Methods Relevant studies on NUDT 15 polymorphism were searched from the electronic databases before 3 March 2018. The overall pooled ORs and corresponding 95% Cis was used.
Results 16 independent studies (4458 subjects) were included in our system review and meta-analysis. We found significant associations between NUDT 15 c.415C＞T polymorphism and leukopenia in all genetic model (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, homozygote, and co-dominant model), leukopenia (grade 3-4) and severe hair loss in all genetic model. Besides, c.52G＞A and 36_37insGGAGTC polymorphism were also significantly associated with leukopenia (GA vs. GG, OR: 3.52, 95% CI (1.52, 8.17), P=0.003; -/ins vs. -/-, OR: 3.84, 95% CI: (2.50, 5.91), P＜0.00001). No significant association between NUDT 15 c.415C＞T polymorphism and early/late leukopenia in Chinese population in co-dominant model (TC vs CC, OR: 1.70, 95% CI: (0.89, 3.22), P=0.11; OR: 0.59, 95% CI: (0.31, 1.12), P=0.11).
Conclusion
This system review and meta-analysis confirm that three genotypes of NUDT 15 polymorphism is significantly associated with thiopurine-induced leukopenia in Asian. Preemptive test for NUDT 15 polymorphism is highly recommended to individualize the treatment of thiopurines with less toxicity and better outcome.