Abstract
Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author’s name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11–18.35) and 16.35 (95% CI 10.20–26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65–24.27) and early neutropenia (OR 15.85; 95% CI 8.80–28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99–708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.
Highlights
Thiopurines, 6-mercaptopurine (6-MP) and azathioprine (AZA), are purine analogs that are closely related in their structures (Coulthard and Hogarth, 2005). 6-MP is widely used in the treatment of acute lymphoblastic leukemia (ALL) as part of a combination regimen at the maintenance phase and used as an immunosuppressive agent for maintaining the remission of the disease
A total of 431 studies were identified from an updated literature search while an additional seven studies from a previous systematic meta-analysis by Zhang et al (2018) were reviewed
Of the original 431 articles, 30 studies were included in the metaanalysis
Summary
Thiopurines, 6-mercaptopurine (6-MP) and azathioprine (AZA), are purine analogs that are closely related in their structures (Coulthard and Hogarth, 2005). 6-MP is widely used in the treatment of acute lymphoblastic leukemia (ALL) as part of a combination regimen at the maintenance phase and used as an immunosuppressive agent for maintaining the remission of the disease. AZA is commonly used in management of autoimmune disorders e.g. Crohn’s disease, rheumatoid arthritis, and systemic lupus erythematosus (SLE) (Zaza et al, 2010), whereas thiopurine drugs have been shown to be effective in maintaining disease remission; almost 30–40% of patients discontinue therapy due to adverse effects, myelosuppression (Lee et al, 2015), in which its incidence is higher in Asian populations than in Caucasian populations (Kakuta et al, 2018b). Thiopurine-induced myelosuppression often causes infectious complications and some patients require therapy interruption leading to suboptimal treatment and unfavorable outcomes (Relling et al, 1999; Hindorf et al, 2006). These adverse effects are known to be caused by individual differences in thiopurine metabolism, which is affected by the genetic variations. NUDT15 enzyme dephosphorylates 6TGN prevent the incorporation into DNA or RNA (Moriyama et al, 2016) decreasing of the enzymatic activity which observed in NUDT15 variants, NUDT15*3 was leading to thiopurine-induced myelosuppression (Moriyama et al, 2016)
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