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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

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          Abstract

          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.

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          Most cited references 31

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          NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

          Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.
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            The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.

            Thiopurine methyltransferase metabolizes 6-mercaptopurine, thioguanine and azathioprine, thereby regulating cytotoxicity and clinical response to these thiopurine drugs. In healthy Caucasian populations, 89-94% of individuals have high thiopurine methyltransferase activity, 6-11% intermediate and 0.3% low, resulting from genetic polymorphism. Four variant thiopurine methyltransferase alleles were detected in over 80% of individuals with low or intermediate thiopurine methyltransferase activity. The wild-type allele is defined as TPMT*1 and the mutant alleles are TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3B (A719G). The frequency of these alleles in different ethnic groups is not well defined. In this study, DNA from 199 British Caucasian, 99 British South West Asian and 192 Chinese individuals was analysed for the presence of these variant alleles using polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction based assays. The frequency of individuals with a variant thiopurine methyltransferase genotype was: Caucasians 10.1% (20/199), South West Asians 2.0% (2/99) and Chinese 4.7% (9/192). Two TPMT*2 heterozygotes were identified in the Caucasian population, but this allele was not found in the two Asian populations. TPMT*3A was the only mutant allele found in the South West Asians (two heterozygotes). This was also the most common mutant allele in the Caucasians (16 heterozygotes and one homozygote) but was not found in the Chinese. All mutant alleles identified in the Chinese population were TPMT*3C (nine heterozygotes). This allele was found at a low frequency in the Caucasians (one heterozygote). This suggests that A719G is the oldest mutation, with G460A being acquired later to form the TPMT*3A allele in the Caucasian and South West Asian populations. TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date. These ethnic differences may be important in the clinical use of thiopurine drugs.
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              Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

               Antje Timmer (corresponding) ,  Petrease Patton,  Nilesh Chande (2016)
              Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                05 August 2019
                2019
                : 13
                : 2729-2744
                Affiliations
                [1 ]Clinical Research Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University , Beijing, People’s Republic of China
                [2 ]Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Capital Medical University , Beijing, People’s Republic of China
                Author notes
                Correspondence: Zhigang ZhaoDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University , 6 TiantanXili, Dongcheng District, Beijing100050, People’s Republic of ChinaTel +86 106 709 8036Fax +86 106 709 6867Email ttyyzzg1022@126.com
                Libo ZhaoClinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health , 56 Nanlishi Road, Xicheng District, Beijing100045, People’s Republic of ChinaTel +86 105 961 6083Fax +86 105 961 6083Email libozhao2011@163.com
                Article
                210512
                10.2147/DDDT.S210512
                6689127
                © 2019 Wang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, Tables: 4, References: 36, Pages: 16
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