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Stanton MB, Solinski MA, Hanauer SB. Genetic polymorphisms impacting clinical pharmacology of drugs used to treat inflammatory bowel disease: a precursor to multi-omics approach to precision medicine. Expert Rev Clin Immunol 2025; 21:461-472. [PMID: 39885730 DOI: 10.1080/1744666x.2025.2461584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 01/29/2025] [Indexed: 02/01/2025]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBDs), comprised of ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. Clinicians and patients must vigilantly manage these complex diseases over the course of the patient's lifetime to mitigate risks of the disease, surgical complications, progression to neoplasia, and complications from medical or surgical therapies. Over the past several decades, the armamentarium of IBD therapeutics has expanded; now with biologics and advanced small molecules complementing conventional drugs such as aminosalicylates, corticosteroids and thiopurines. Significant attention has been paid to the potential of precision medicine to assist clinicians in tailoring therapeutics based on patients' genetic signatures to maximize therapeutic benefit while minimizing adverse effects. AREAS COVERED In this paper, we review the published literature on genetic polymorphisms relevant to each class of IBD therapeutics. EXPERT OPINION Finally, we envision a paradigm shift in IBD research toward an omics-based network analysis approach. Through global collaboration, organization and goal setting, we predict the next decade of IBD research will revolutionize existing disease frameworks by developing precise molecular diagnoses, validated biomarkers, predictive models and novel molecularly targeted therapeutics.
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Affiliation(s)
- Matthew B Stanton
- Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, IL, USA
| | - Mark A Solinski
- Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, IL, USA
| | - Stephen B Hanauer
- Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, IL, USA
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Kakuta Y, Kato M, Shimoyama Y, Naito T, Moroi R, Kuroha M, Shiga H, Kinouchi Y, Masamune A. Usefulness and difficulties with the thiopurine pharmacogenomic NUDT15 genotyping test: Analysis of real-world data in Japan. J Pharmacol Sci 2023; 153:161-169. [PMID: 37770157 DOI: 10.1016/j.jphs.2023.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/17/2023] [Accepted: 09/08/2023] [Indexed: 10/03/2023] Open
Abstract
The usefulness of NUDT15 genotyping as a pharmacogenomic test for thiopurine has been established. The first such test developed to date, NUDT15 genotyping was approved for reimbursement in Japan in February 2019 for all indicated patients. We retrospectively examined claims data in Japan and confirmed that the proportion of patients who undergo genotyping before initiating a new thiopurine regimen has increased; furthermore, genotyping has improved the rate of treatment continuation and reduced on-treatment hospitalization. However, the genotyping rate before thiopurine induction was >50% for patients with inflammatory bowel disease and <20% for those with other immune-related diseases, indicating significant variation by disease field. Additionally, over 10% of tests were found to have been performed inappropriately, such as multiple genotyping of the same patient or testing more than 2 weeks after starting treatment. Although NUDT15 genotyping for patients requiring thiopurine treatment has been shown to improve thiopurine treatment continuation rate, measures are required to address the systematic issues identified in our analysis.
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Affiliation(s)
- Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Motohiro Kato
- Department of Pediatrics, University of Tokyo, Tokyo, Japan
| | - Yusuke Shimoyama
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitaka Kinouchi
- Student Healthcare Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Ribeiro AC, Gerheim PSAS, Chebli JMF, Nascimento JWL, de Faria Pinto P. The Role of Pharmacogenetics in the Therapeutic Response to Thiopurines in the Treatment of Inflammatory Bowel Disease: A Systematic Review. J Clin Med 2023; 12:6742. [PMID: 37959208 PMCID: PMC10649589 DOI: 10.3390/jcm12216742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/26/2023] [Accepted: 10/07/2023] [Indexed: 11/15/2023] Open
Abstract
This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.
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Affiliation(s)
- Aline C. Ribeiro
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Minas Gerais, Brazil;
| | - Pâmela S. A. S. Gerheim
- Department of Pharmacology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Minas Gerais, Brazil;
| | - Julio Maria Fonseca Chebli
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Minas Gerais, Brazil;
| | - Jorge Willian L. Nascimento
- Laboratory of Clinical and Experimental Pharmacology, Department of Pharmacology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Minas Gerais, Brazil
| | - Priscila de Faria Pinto
- Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Minas Gerais, Brazil
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Suzuki S, Uchiyama K, Motoi Y, Yoshii Y, Inoue Y, Kubota T, Odahara S, Ohtaki Y, Takami S, Ito Z, Sato N, Ohkusa T, Koido S, Saruta M. Analysis of the NUDT15 gene and metabolites of azathioprine in Japanese patients with inflammatory bowel disease. BMC Gastroenterol 2023; 23:239. [PMID: 37454061 DOI: 10.1186/s12876-023-02881-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. METHODS To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study. RESULTS The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms. CONCLUSIONS All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.
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Affiliation(s)
- Shizuka Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan.
| | - Yutaro Motoi
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Yuuki Yoshii
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Yukari Inoue
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Takahiro Kubota
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, F103a, 265-1 Higashijima, Akiha-Ku, Niigata City, 956-8603, Japan
| | - Shunichi Odahara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Yuichiro Ohtaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Shinichiro Takami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Ochanomizu KS Building 4F 405 Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Toshifumi Ohkusa
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Ochanomizu KS Building 4F 405 Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, 163-1 Kashiwa, Kashiwa-Shi, Chiba, 277-8567, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-19-18 Nishishinbashi, Minato-Ku, Tokyo, 105-0003, Japan
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Isono T, Hira D, Ikeda Y, Kawahara M, Noda S, Nishida A, Inatomi O, Fujimoto N, Andoh A, Terada T, Morita SY. Single-Nucleotide Polymorphisms, c.415C > T (Arg139Cys) and c.416G > A (Arg139His), in the NUDT15 Gene Are Associated with Thiopurine-Induced Leukopenia. Biol Pharm Bull 2023; 46:412-418. [PMID: 36858569 DOI: 10.1248/bpb.b22-00686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023]
Abstract
While nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphism Arg139Cys (rs116855232) is known to be a risk factor for thiopurine-induced severe leukopenia, association with the NUDT15 gene polymorphism Arg139His (rs147390019) has not yet been clarified. In addition, the accuracy of TaqMan PCR to assess these two polymorphisms has not been investigated. In this study, we evaluated TaqMan PCR for detection of the NUDT15 single-nucleotide polymorphisms (SNPs) and examined the clinical impact of Arg139His on thiopurine-induced leukopenia. First, we demonstrated that a TaqMan PCR assay successfully detected the Arg139His polymorphism of NUDT15 in clinical samples. Next, the NUDT15 gene polymorphisms (Arg139Cys and Arg139His) were separately analyzed by TaqMan Real-Time PCR in 189 patients from August 2018 to July 2019. The incidences of leukopenia within 2 years were 16.2, 57.9, and 100% for arginine (Arg)/Arg, Arg/cysteine (Cys), and Arg/histidine (His), respectively. The leukopenia was significantly increased in Arg/Cys and Arg/His compared with Arg/Arg. This retrospective clinical study indicated that, in addition to Arg139Cys, Arg139His may be clinically associated with a high risk of leukopenia. Pharmacogenomics will help in selecting drugs and determining the individualized dosage of thiopurine drugs.
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Affiliation(s)
- Tetsuichiro Isono
- Department of Pharmacy, Shiga University of Medical Science Hospital
| | - Daiki Hira
- Department of Pharmacy, Shiga University of Medical Science Hospital.,Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital.,College of Pharmaceutical Sciences, Ritsumeikan University
| | - Yoshito Ikeda
- Department of Pharmacy, Shiga University of Medical Science Hospital
| | - Masahiro Kawahara
- Department of Gastroenterology and Hematology, Shiga University of Medical Science
| | - Satoshi Noda
- Department of Pharmacy, Shiga University of Medical Science Hospital
| | - Atsushi Nishida
- Department of Gastroenterology and Hematology, Shiga University of Medical Science
| | - Osamu Inatomi
- Department of Gastroenterology and Hematology, Shiga University of Medical Science
| | - Noriki Fujimoto
- Department of Dermatology, Shiga University of Medical Science
| | - Akira Andoh
- Department of Gastroenterology and Hematology, Shiga University of Medical Science
| | - Tomohiro Terada
- Department of Pharmacy, Shiga University of Medical Science Hospital.,Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
| | - Shin-Ya Morita
- Department of Pharmacy, Shiga University of Medical Science Hospital
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Heidari M, Khalili M, Malek Hosseini SA, Geramizadeh B, Shamsaefar AR, Balouchi F, Karimi MH. Investigation of the Association Between the ITPA Gene 94C>A Gene Sequence Variant and Liver Transplant Rejection in Iranian Liver Transplant Recipients. EXP CLIN TRANSPLANT 2022; 20:1094-1098. [PMID: 36718008 DOI: 10.6002/ect.2022.0362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of thiopurine nucleotides into DNA and RNA. Thiopurine drug metabolites such as azathioprine and 6-mercaptopurine have been included in the lists of inosine triphosphate pyrophosphatase substrates. Inosine triphosphatase gene alterations are other pharmacogenetic sequence variants possibly involved in thiopurine metabolism. This study aimed to evaluate the possible association between ITPA 94C>A gene sequence variant (C-to-A substitution at nucleotide 94) in liver transplant recipients. MATERIALS AND METHODS The genotyping of ITPA 94C>A was evaluated by the polymerase chain reaction- restriction fragment length polymorphism method in 200 liver transplant recipients as well as 100 controls. Data were analyzed with SPSS statistical software. RESULTS This study showed statistically significant associations between the CA genotype of the ITPA 94C>A sequence variant and liver transplant in the rejection and nonrejection groups. Moreover, the results reported in this study showed no significant differences between sex, age, and blood group in patients with liver transplant (with or without transplant rejection). CONCLUSIONS Our results indicated that there were statistically significant associations of the CA genotype of ITPA 94C>A sequence variant with liver transplant in the rejection and nonrejection groups. Further studies are recommended.
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Affiliation(s)
- Mozhdeh Heidari
- From the Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Guo HL, Zhao YT, Wang WJ, Dong N, Hu YH, Zhang YY, Chen F, Zhou L, Li T. Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring. Front Pharmacol 2022; 13:941182. [PMID: 36238550 PMCID: PMC9552076 DOI: 10.3389/fphar.2022.941182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.
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Affiliation(s)
- Hong-Li Guo
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yue-Tao Zhao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Visiting Graduate Student from School of Basic Medicine and Clinical Pharmacy, Pharmaceutical University, Nanjing, China
| | - Wei-Jun Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Visiting Graduate Student from School of Basic Medicine and Clinical Pharmacy, Pharmaceutical University, Nanjing, China
| | - Na Dong
- Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China
- School of Institute of Pharmaceutical Science, Pharmaceutical University, Nanjing, China
| | - Ya-Hui Hu
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan-Yuan Zhang
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Chen
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Feng Chen, ; Li Zhou, ; Tao Li,
| | - Li Zhou
- Hematology and Oncology Department, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Feng Chen, ; Li Zhou, ; Tao Li,
| | - Tao Li
- Department of Solid Oncology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Feng Chen, ; Li Zhou, ; Tao Li,
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Luo X, Yan S, Jin L, Zhu H, Zhang X, Ge W. Inosine Triphosphate Pyrophosphatase and NUDT15 are Good Predictors of Clinical Outcomes in Thiopurine-Treated Chinese Patients with Inflammatory Bowel Disease. Ther Drug Monit 2022; 44:391-395. [PMID: 35067667 DOI: 10.1097/ftd.0000000000000965] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/07/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Although the relationship between NUDT15 and thiopurine-induced leukopenia has been proven in previous studies, no prominent factors explaining interindividual variations in its active metabolite, 6-thioguanine nucleotide (6-TGN), and clinical efficacy have been identified. In this study, the correlation between genotypes (thiopurine S-methyltransferase, NUDT15, and ITPA polymorphisms), 6-TGN concentrations, and clinical outcomes (efficacy and side effects) in patients with inflammatory bowel disease were investigated. METHODS In total, 160 patients with inflammatory bowel disease were included, and the 3 genotyped genes and 6-TGN levels were measured by high-performance liquid chromatography. Statistical analyses and calculations were performed to determine their relationships. RESULTS ITPA genotypes and 6-TGN concentration were both associated with the clinical effectiveness of azathioprine (P = 0.036 and P = 4.6 × 10-7), with a significant correlation also detected between them (P = 0.042). Patients with ITPA variant alleles exhibited higher 6-TGN levels than those with the wild-type allele. In addition, the relationship between NUDT15 and leukopenia and neutropenia was confirmed (P = 1.79 × 10-7 and 0.002). CONCLUSIONS In summary, it is recommended that both ITPA and NUDT15 genotyping should be performed before azathioprine initiation. Moreover, the 6-TGN concentration should be routinely monitored during the later period of treatment.
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Affiliation(s)
- Xuemei Luo
- Department of Medication, The Affiliated Drum Tower Hospital of Nanjing University Medical School; and
- Nanjing Medical Center for Clinical Pharmacy, and
| | - Simin Yan
- Department of Medication, The Affiliated Drum Tower Hospital of Nanjing University Medical School; and
- Nanjing Medical Center for Clinical Pharmacy, and
| | - Lu Jin
- Department of Medication, The Affiliated Drum Tower Hospital of Nanjing University Medical School; and
- Nanjing Medical Center for Clinical Pharmacy, and
| | - Huaijun Zhu
- Department of Medication, The Affiliated Drum Tower Hospital of Nanjing University Medical School; and
- Nanjing Medical Center for Clinical Pharmacy, and
| | - Xiaoqi Zhang
- Department of Medication, The Affiliated Drum Tower Hospital of Nanjing University Medical School; and
- Nanjing Medical Center for Clinical Pharmacy, and
| | - Weihong Ge
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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Lee Y, Jang EJ, Yoon HY, Yee J, Gwak HS. Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel) 2022; 15:ph15040416. [PMID: 35455413 PMCID: PMC9027773 DOI: 10.3390/ph15040416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56−3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32−2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74−4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity.
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Affiliation(s)
- Yeonhong Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
- Department of Pharmacy, National Cancer Center, Goyang-si 10408, Korea
| | - Eun Jeong Jang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
| | - Ha-Young Yoon
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
| | - Jeong Yee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
| | - Hye-Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
- Correspondence: ; Tel.: +82-2-3277-4376; Fax: +82-2-3277-3051
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10
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Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis. THE PHARMACOGENOMICS JOURNAL 2022; 22:39-54. [PMID: 35034963 DOI: 10.1038/s41397-021-00255-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/24/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023]
Abstract
Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97-2.90, and OR: 2.43, 95%CI: 2.12-2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22-3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36-3.63, and OR: 2.82, 95%CI: 1.76-4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06-2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.
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11
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Khaeso K, Komvilaisak P, Chainansamit SO, Nakkam N, Suwannaying K, Kuwatjanakul P, Hikino K, Dornsena A, Kanjanawart S, Laoaroon N, Vannaprasaht S, Taketani T, Tassaneeyakul W. NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine. Drug Metab Pharmacokinet 2021; 43:100436. [PMID: 35016134 DOI: 10.1016/j.dmpk.2021.100436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/21/2021] [Accepted: 11/25/2021] [Indexed: 12/25/2022]
Abstract
6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15∗3 and NUDT15∗2 genotypes were at a 10-15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15∗3 and NUDT15∗2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.
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Affiliation(s)
- Kanyarat Khaeso
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand
| | | | | | - Nontaya Nakkam
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand
| | - Kunanya Suwannaying
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Thailand
| | | | - Keiko Hikino
- Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Areerat Dornsena
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand
| | - Sirimas Kanjanawart
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand
| | - Napat Laoaroon
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Thailand
| | - Suda Vannaprasaht
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand
| | - Takeshi Taketani
- Department of Pediatrics, Faculty of Medicine, Shimane University, Izumo, Japan
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12
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Andoh A, Kawahara M, Imai T, Tatsumi G, Inatomi O, Kakuta Y. Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease. J Gastroenterol 2021; 56:881-890. [PMID: 34287682 DOI: 10.1007/s00535-021-01805-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/18/2021] [Indexed: 02/04/2023]
Abstract
The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 p.Arg139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knock-in mice harboring the p.Arg138Cys mutation which corresponds to human p.Arg139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.
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Affiliation(s)
- Akira Andoh
- Division of Gastroenterology and Hematology, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan.
| | - Masahiro Kawahara
- Division of Gastroenterology and Hematology, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Takayuki Imai
- Division of Gastroenterology and Hematology, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Goichi Tatsumi
- Division of Gastroenterology and Hematology, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Osamu Inatomi
- Division of Gastroenterology and Hematology, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan
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13
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Rosdiana DS, Setiabudy R, Andalusia R, Gatot D, Louisa M, Bardosono S, Instiaty I. TPMT Genetic Variability and Its Association with Hematotoxicity in Indonesian Children with Acute Lymphoblastic Leukemia in Maintenance Therapy. Pharmgenomics Pers Med 2021; 14:199-210. [PMID: 33568932 PMCID: PMC7868246 DOI: 10.2147/pgpm.s288988] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/29/2020] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Hematotoxicity monitoring in children with acute lymphoblastic leukemia (ALL) is critical to preventing life-threatening infections and drug discontinuation. The primary drug that causes hematotoxicity in ALL children is 6-mercaptopurine (6-MP). Genetic variability of the drug-metabolizing enzymes of 6-MP, thiopurine S-methyltransferase (TPMT), is one factor that might increase the susceptibility of children to hematotoxicity. The present study aimed to determine the variability in TPMT genotypes and phenotypes and its association with the occurrence of hematotoxicity in ALL children in maintenance therapy. PATIENTS AND METHODS A cross-sectional study was conducted at Cipto Mangunkusumo and Dharmais National Cancer Hospital, Jakarta, Indonesia, from June 2017 to October 2018. We included ALL patients, 1-18 years, who were receiving at least one month of 6-MP during maintenance therapy according to the Indonesian protocol for ALL 2013. Direct sequencing was used to determine TPMT*3A, *3B, and *3C genotypes, and LC-MS/MS analysis was performed to measure the plasma concentrations of 6-MP and its metabolites. Association analysis between the TPMT genotype and hematotoxicity was evaluated using the unpaired t-test or Mann-Whitney's test. RESULTS The prevalence of neutropenia, anemia, and thrombocytopenia in ALL children during maintenance therapy was 51.9%, 44.3%, and 6.6%, respectively. We found a low frequency of TPMT*3C, which is 0.95%. No association was found between hematotoxicity and TPMT genotypes or age, nutritional status, serum albumin levels, risk stratification, the daily dose of 6-MP, and cotrimoxazole co-administration. However, hematotoxicity was associated with 6-methylmercaptopurine (6-MeMP) plasma concentrations and the ratio 6-MeMP/6-thioguanine (6-TGN). We also found no association between TPMT genotypes and TPMT phenotypes. CONCLUSION The 6-MeMP/6-TGN ratio is associated with hematotoxicity in ALL children during maintenance therapy but is not strong enough to predict hematotoxicity.
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Affiliation(s)
- Dewi Selvina Rosdiana
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Rianto Setiabudy
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Rizka Andalusia
- Dharmais National Cancer Hospital, Jakarta, Indonesia
- Drug Registration Directorate, National Agency for Drug and Food Control, Jakarta, Indonesia
| | - Djajadiman Gatot
- Division of Hematology-Oncology, Department of Pediatrics, Faculty of Medicine, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Melva Louisa
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Saptawati Bardosono
- Department of Nutrition, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Instiaty Instiaty
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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14
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Lin R, Lin W, Wang C, Dong J, Zheng W, Zeng D, Liu Y, Lin C, Jiao Z, Huang P. Population pharmacokinetics of azathioprine active metabolite in patients with inflammatory bowel disease and dosage regimens optimisation. Basic Clin Pharmacol Toxicol 2020; 128:482-492. [PMID: 33150655 DOI: 10.1111/bcpt.13530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/12/2020] [Accepted: 11/02/2020] [Indexed: 12/25/2022]
Abstract
Azathioprine is a first-line drug used to maintain the remission of inflammatory bowel disease (IBD). As a prodrug, azathioprine is metabolised to produce active 6-thioguanine nucleotides (6-TGN). There are large individual variations in the pharmacokinetics/pharmacodynamics of 6-TGN in patients with IBD. Here, we aimed to develop a model to quantitatively investigate factors that affect 6-TGN pharmacokinetics to formulate a dosage guideline for azathioprine. Data were collected prospectively from 100 adult patients with IBD who were receiving azathioprine. Patients were genotyped for two single-nucleotide polymorphisms (TPMT*3C c.719A > G and NUDT15 c.415C > T). Using high-performance liquid chromatography, we measured 156 steady-state trough concentrations of 6-TGN within the range 0.09 to 1.16 mg/L (ie 133-1733 pmol per 8 × 108 RBC). The covariates analysed included sex, age, body-weight, laboratory tests and concomitant medications. A population pharmacokinetic model was established using "non-linear mixed-effects modelling" software and the "first-order conditional estimation method with interaction." Body-weight, TPMT*3C polymorphisms and co-therapy with mesalazine were found to be important factors influencing the clearance of 6-TGN. A dosage guideline for azathioprine was developed based on the PPK model that enables individualised azathioprine dosing in adult patients with different body-weights, TPMT*3C genotypes and co-administration with mesalazine.
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Affiliation(s)
- Rongfang Lin
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Weiwei Lin
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Changlian Wang
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jiashan Dong
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Weiwei Zheng
- Department of Gastroenterology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Dayong Zeng
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yiwei Liu
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Cuihong Lin
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zheng Jiao
- Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Pinfang Huang
- Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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15
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Akiyama S, Matsuoka K, Fukuda K, Hamada S, Shimizu M, Nanki K, Mizuno S, Kiyohara H, Arai M, Sugimoto S, Iwao Y, Ogata H, Hisamatsu T, Naganuma M, Motobayashi M, Suzuki K, Takenaka K, Fujii T, Saito E, Nagahori M, Ohtsuka K, Mochizuki M, Watanabe M, Hashiguchi M, Kanai T. Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine. J Gastroenterol Hepatol 2019; 34:1751-1757. [PMID: 31045285 DOI: 10.1111/jgh.14693] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 04/08/2019] [Accepted: 04/20/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.
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Affiliation(s)
- Shintaro Akiyama
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan
| | - Kyoko Fukuda
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Shunsuke Hamada
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Mikiko Shimizu
- Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Kosaku Nanki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Shinta Mizuno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Mari Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Shinya Sugimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yasushi Iwao
- Department of Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Maiko Motobayashi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kohei Suzuki
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Takenaka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masakazu Nagahori
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuo Ohtsuka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mayumi Mochizuki
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masayuki Hashiguchi
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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16
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Kishibe M, Nozaki H, Fujii M, Iinuma S, Ohtsubo S, Igawa S, Kanno K, Honma M, Kishibe K, Okamoto K, Ishida-Yamamoto A. Severe thiopurine-induced leukocytopenia and hair loss in Japanese patients with defectiveNUDT15 variant: Retrospective case-control study. J Dermatol 2018; 45:1160-1165. [DOI: 10.1111/1346-8138.14588] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 07/03/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Mari Kishibe
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Hiroyoshi Nozaki
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Mizue Fujii
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Shin Iinuma
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Sawa Ohtsubo
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Satomi Igawa
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Kyoko Kanno
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Masaru Honma
- Department of Dermatology; Asahikawa Medical University; Asahikawa Japan
| | - Kan Kishibe
- Department of Otorhinolaryngology; Asahikawa Medical University; Asahikawa Japan
| | - Kensaku Okamoto
- Division of Metabolism and Biosystemic Science; Department of Medicine; Asahikawa Medical University; Asahikawa Japan
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17
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ITPA Activity in Adults and Children Treated With or Without Azathioprine: Relationship Between TPMT Activity, Thiopurine Metabolites, and Co-medications. Ther Drug Monit 2018. [PMID: 28650902 DOI: 10.1097/ftd.0000000000000430] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data are available on its role on thiopurine metabolites. The ability of ITPA to modify the thiopurine metabolite levels is currently used to optimize azathioprine (AZA) therapy in relation to thiopurine S-methyltransferase (TPMT) activity, the aim of this study is to investigate ITPA phenotype in a large population and to evaluate the relation between ITPA and TPMT activities and thiopurine metabolites. METHODS ITPA activity was determined in 183 adults and 138 children with or without AZA therapy. 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotides (6-MeMPN) levels, and ITPA as well as TPMT activities were measured in red blood cells. Using the Gaussian mixture model, distribution of ITPA activity was evaluated. Intraindividual variability and influence of age, sex, AZA treatment and associated co-medications on ITPA activity were also assessed. RESULTS This retrospective study shows a quadrimodal distribution in ITPA activity. No influence of age, sex, AZA therapy, and co-medications was found. In adults, ITPA activity was not significantly associated with 6-TGN or 6-MeMPN concentrations, whereas a weak negative correlation was observed with 6-MeMPN levels in pediatric populations (rs = -0.261; P = 0.024). A weak positive correlation was observed between ITPA and TPMT activities in children (rs = 0.289; P = 0.001). CONCLUSIONS ITPA activity was poorly influenced by nongenetic parameters and has no influence on 6-TGN and 6-MeMPN concentrations in adults and only a weak correlation with 6-MeMPN and TPMT activity in children. These results demonstrate that ITPA is not a rate-limiting enzyme in the formation of 6-TGN but suggest that a decrease in ITPA activity in children may be a risk factor for accumulation of 6-MeMPN in cells.
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18
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Citterio-Quentin A, Moulsma M, Gustin MP, Lachaux A, Boulieu R. ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response. Basic Clin Pharmacol Toxicol 2018; 122:588-595. [PMID: 29327413 DOI: 10.1111/bcpt.12958] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/27/2017] [Indexed: 12/13/2022]
Abstract
Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.
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Affiliation(s)
- Antony Citterio-Quentin
- UMR CNRS 5305, Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Université de Lyon, Université Lyon 1, Lyon, France.,Edouard Herriot Hospital, Laboratory of Medical Biology Multi Sites of the University Hospital of Lyon, Pharmaco-Toxicology Unit, Civil Hospices of Lyon, Lyon, France
| | - Mustapha Moulsma
- Edouard Herriot Hospital, Laboratory of Medical Biology Multi Sites of the University Hospital of Lyon, Pharmaco-Toxicology Unit, Civil Hospices of Lyon, Lyon, France
| | - Marie-Paule Gustin
- Emerging pathogen Laboratory - Fondation Mérieux, Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Lyon, France
| | - Alain Lachaux
- Pediatric Gastroenterology Unit, Civil Hospices of Lyon, Hôpital Femme-Mère-Enfant (HFME), Lyon, France
| | - Roselyne Boulieu
- UMR CNRS 5305, Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Université de Lyon, Université Lyon 1, Lyon, France.,Edouard Herriot Hospital, Laboratory of Medical Biology Multi Sites of the University Hospital of Lyon, Pharmaco-Toxicology Unit, Civil Hospices of Lyon, Lyon, France
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19
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Kakuta Y, Kinouchi Y, Shimosegawa T. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping. J Gastroenterol 2018; 53:172-180. [PMID: 29192347 PMCID: PMC5846876 DOI: 10.1007/s00535-017-1416-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 11/19/2017] [Indexed: 02/06/2023]
Abstract
The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn's disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned.
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Affiliation(s)
- Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Yoshitaka Kinouchi
- Institute for Excellent in Higher Education, Tohoku University, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
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Kakuta Y, Kawai Y, Okamoto D, Takagawa T, Ikeya K, Sakuraba H, Nishida A, Nakagawa S, Miura M, Toyonaga T, Onodera K, Shinozaki M, Ishiguro Y, Mizuno S, Takahara M, Yanai S, Hokari R, Nakagawa T, Araki H, Motoya S, Naito T, Moroi R, Shiga H, Endo K, Kobayashi T, Naganuma M, Hiraoka S, Matsumoto T, Nakamura S, Nakase H, Hisamatsu T, Sasaki M, Hanai H, Andoh A, Nagasaki M, Kinouchi Y, Shimosegawa T, Masamune A, Suzuki Y. NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. J Gastroenterol 2018; 53:1065-1078. [PMID: 29923122 PMCID: PMC6132901 DOI: 10.1007/s00535-018-1486-7] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 06/13/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. METHODS Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. RESULTS We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). CONCLUSIONS Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.
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Affiliation(s)
- Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Yosuke Kawai
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan ,Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Daisuke Okamoto
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Tetsuya Takagawa
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kentaro Ikeya
- Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Atsushi Nishida
- Department of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Shoko Nakagawa
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Miki Miura
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Takahiko Toyonaga
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Kei Onodera
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaru Shinozaki
- Department of Surgery, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoh Ishiguro
- Department of Gastroenterology and Hematology, Hirosaki National Hospital, Hirosaki, Japan
| | - Shinta Mizuno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Shunichi Yanai
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryota Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan
| | - Tomoo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroshi Araki
- Division of Endscopy, Gifu University Hospital, Gifu, Japan
| | - Satoshi Motoya
- IBD Center, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Katsuya Endo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Shiro Nakamura
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Makoto Sasaki
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hiroyuki Hanai
- Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
| | - Akira Andoh
- Department of Gastroenterology, Shiga University of Medical Science, Otsu, Japan
| | - Masao Nagasaki
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Yoshitaka Kinouchi
- Health Administration Center, Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574 Japan
| | - Yasuo Suzuki
- Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan
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Rufini S, Ciccacci C, Novelli G, Borgiani P. Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease. Pharmacogenomics 2017; 18:1095-1114. [PMID: 28686143 DOI: 10.2217/pgs-2017-0068] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.
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Affiliation(s)
- Sara Rufini
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
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Moon W, Loftus EV. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2016; 43:863-883. [PMID: 26876431 DOI: 10.1111/apt.13559] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 08/26/2015] [Accepted: 01/26/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Azathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount. AIM To provide a comprehensive review focused on pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in IBD. METHODS A literature search up to July 2015 was performed in PubMed using a combination of relevant MeSH terms. RESULTS Pre-treatment thiopurine S-methyltransferase typing plus measurement of 6-tioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels during treatment have emerged with key roles in facilitating safe and effective thiopurine therapy. Optimal use of these tools has been shown to reduce the risk of adverse effects by 3-7%, and to improve efficacy by 15-30%. For the introduction of aldehyde oxidase (AOX) into clinical practice, the association between AOX activity and AZA dose requirements should be positively confirmed. Inosine triphosphatase assessment associated with adverse effects also shows promise. Nucleoside diphosphate-linked moiety X-type motif 15 variants have been shown to predict myelotoxicity on thiopurines in East Asian patients. However, the impact of assessments of xanthine oxidase, glutathione S-transferase, hypoxanthine guanine phosphoribosyltransferase and inosine monophosphate dehydrogenase appears too low to favour incorporation into clinical practice. CONCLUSIONS Measurement of thiopurine-related enzymes and metabolites reduces the risk of adverse effects and improves efficacy, and should be considered part of standard management. However, this approach will not predict or avoid all adverse effects, and careful clinical and laboratory monitoring of patients receiving thiopurines remains essential.
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Affiliation(s)
- W Moon
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.,Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - E V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol 2016; 51:22-9. [PMID: 26590936 DOI: 10.1007/s00535-015-1142-4] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 10/27/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD). METHODS Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays. RESULTS The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 × 10(-5)). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 × 10(-4)) and late (>8 weeks) leukocytopenia (P = 4.3 × 10(-4)). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001). CONCLUSIONS These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.
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Azimi F, Esmaeilzadeh A, Ramazani A. RETRACTED: Clinical significance of ITPA rs67002563 polymorphism in patients with acute lymphoblastic leukemia treated with 6-mercaptopurine. Pharmacol Res 2015; 102:61-2. [DOI: 10.1016/j.phrs.2015.09.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 09/18/2015] [Accepted: 09/18/2015] [Indexed: 11/25/2022]
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Gómez-Gómez GJ, Masedo &A, Yela C, Martínez-Montiel MDP, Casís B. Current stage in inflammatory bowel disease: What is next? World J Gastroenterol 2015; 21:11282-11303. [PMID: 26525013 PMCID: PMC4616205 DOI: 10.3748/wjg.v21.i40.11282] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/12/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.
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Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects. Leuk Res 2015; 39:1048-54. [DOI: 10.1016/j.leukres.2015.06.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 06/23/2015] [Accepted: 06/29/2015] [Indexed: 01/29/2023]
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Coenen MJH, de Jong DJ, van Marrewijk CJ, Derijks LJJ, Vermeulen SH, Wong DR, Klungel OH, Verbeek ALM, Hooymans PM, Peters WHM, te Morsche RHM, Newman WG, Scheffer H, Guchelaar HJ, Franke B, Pierik M, Mares W, Hameeteman W, Wahab P, Seinen H, Rijk M, Harkema I, de Bièvre M, Oostenbrug L, Bakker C, Aquarius M, van Deursen C, van Nunen A, Goedhard J, Hamacher M, Gisbertz I, Brenninkmeijer B, Tan A, Aparicio-Pagés M, Witteman E, van Tuyl S, Breumelhof R, Stronkhorst A, Gilissen L, Schoon E, Tjhie-Wensing J, Temmerman A, Nicolaï J, van Bergeijk J, Bac D, Witteman B, Mahmmod N, Uil J, Akol H, Ouwendijk R, van Munster I, Pennings M, De Schryver A, van Ditzhuijsen T, Scheffer R, Römkens T, Schipper D, Bus P, Straathof J, Verhulst M, Boekema P, Kamphuis J, van Wijk H, Salemans J, Vermeijden J, van der Werf S, Verburg R, Spoelstra P, de Vree J, van der Linde K, Jebbink H, Jansen M, Holwerda H, van Bentem N, Kolkman J, Russel M, van Olffen G, Kerbert-Dreteler M, Bargeman M, Götz J, Schröder R, Jansen J, Bos L, Engels L, Romberg-Camps M, Keulen E, van Esch A, Drenth J, van Kouwen M, Wanten G, Bisseling T, Römkens T, van Vugt M, van de Meeberg P, van den Hazel S, Stuifbergen W, Grubben M, de Wit U, Dodemont G, Eichhorn R, van den Brande J, Naber AH, van Soest E, Kingma P, Talstra N, Bruin K, Wolfhagen F, Hommes D, van der Veek P, Hardwick J, Stuyt R, Fidder H, Oldenburg B, Tan T. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology 2015; 149:907-17.e7. [PMID: 26072396 DOI: 10.1053/j.gastro.2015.06.002] [Citation(s) in RCA: 157] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/13/2015] [Accepted: 06/03/2015] [Indexed: 01/11/2023]
Abstract
BACKGROUND & AIMS More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD. METHODS In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]). RESULTS Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85). CONCLUSIONS Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.
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Affiliation(s)
- Marieke J H Coenen
- Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
| | - Dirk J de Jong
- Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Corine J van Marrewijk
- Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Luc J J Derijks
- Department of Clinical Pharmacy, Máxima Medical Centre, Veldhoven, The Netherlands
| | - Sita H Vermeulen
- Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Dennis R Wong
- Department of Clinical Pharmacy and Toxicology, Orbis Medical Center, Sittard-Geleen, The Netherlands
| | - Olaf H Klungel
- Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Andre L M Verbeek
- Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Piet M Hooymans
- Department of Clinical Pharmacy and Toxicology, Orbis Medical Center, Sittard-Geleen, The Netherlands
| | - Wilbert H M Peters
- Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Rene H M te Morsche
- Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - William G Newman
- Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Hans Scheffer
- Department of Human Genetics, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Barbara Franke
- Department of Human Genetics, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands
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Odahara S, Uchiyama K, Kubota T, Ito Z, Takami S, Kobayashi H, Saito K, Koido S, Ohkusa T. A Prospective Study Evaluating Metabolic Capacity of Thiopurine and Associated Adverse Reactions in Japanese Patients with Inflammatory Bowel Disease (IBD). PLoS One 2015; 10:e0137798. [PMID: 26360046 PMCID: PMC4567281 DOI: 10.1371/journal.pone.0137798] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 08/20/2015] [Indexed: 12/26/2022] Open
Abstract
Azathioprine (AZA) is frequently used in patients with inflammatory bowel disease (IBD). However, toxic adverse reactions frequently develop and limit the clinical benefits. Currently, the precise mechanisms underlying thiopurine-related toxicity are not well understood. To investigate the relationship between the extent of thiopurine metabolism and adverse reactions in Japanese IBD patients, we prospectively observed 48 IBD patients who received AZA. We analyzed the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) gene mutations and measured the concentrations of 6-thioguanine nucleotide (6-TGN) continuously for 52 weeks. All patients possessed wild-type TPMT gene sequences. The ITPA 94C>A mutation was detected in 19 patients (39.6%). Adverse reactions developed in 14 of the 48 patients (29.2%), including leukopenia in 10 patients (20.8%). In the leukopenia group, the percentages of patients with 94C>A were higher than those in the without-leukopenia group (70.0% vs. 31.6%, P < 0.05). The average concentrations of 6-TGN in the patients with 94C>A were generally higher than those in the patients without 94C>A, however, there were no significant differences. Only 3 out of 10 patients with leukopenia exhibited high 6-TGN levels (30.0%). No negative correlations between white blood cell (WBC) counts and 6-TGN concentrations were observed. The cumulative incidence of leukopenia were higher for patients with 94C>A. Seven out of 19 patients (36.8%) with the ITPA 94C>A mutation developed leukopenia; however, this mutation may not unequivocally increase the risk of developing leukopenia. In addition, there are factors other than increased 6-TGN levels that are involved in the onset of leukopenia.
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Affiliation(s)
- Shunichi Odahara
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
| | - Kan Uchiyama
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
- * E-mail:
| | - Takahiro Kubota
- Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | - Zensho Ito
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
| | - Shinichiro Takami
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
| | - Hiroko Kobayashi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
| | - Keisuke Saito
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
| | - Shigeo Koido
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
| | - Toshifumi Ohkusa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan
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Roberts RL, Barclay ML. Update on thiopurine pharmacogenetics in inflammatory bowel disease. Pharmacogenomics 2015; 16:891-903. [PMID: 26067482 DOI: 10.2217/pgs.15.29] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.
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Affiliation(s)
- Rebecca L Roberts
- Department of Surgical Sciences, Dunedin School of Medicine, PO Box 56, Dunedin, New Zealand
| | - Murray L Barclay
- Department of Medicine, University of Otago Christchurch, PO Box 4345, Christchurch, New Zealand.,Department of Gastroenterology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand
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Smid A, Karas-Kuzelicki N, Milek M, Jazbec J, Mlinaric-Rascan I. Association of ITPA genotype with event-free survival and relapse rates in children with acute lymphoblastic leukemia undergoing maintenance therapy. PLoS One 2014; 9:e109551. [PMID: 25303517 PMCID: PMC4193781 DOI: 10.1371/journal.pone.0109551] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 09/02/2014] [Indexed: 01/18/2023] Open
Abstract
Although the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, failure due to treatment-related toxicities and relapse of the disease still occur in about 20% of patients. This retrospective study included 308 pediatric ALL patients undergoing maintenance therapy and investigated the effects of genetic variants of enzymes involved in the 6-mercaptopurine (6-MP) metabolism and folate pathway on survival and relapse rates. The presence of at least one of the non-functional ITPA alleles (94C>A and/or IVS2+21A>C variant) was associated with longer event-free survival compared to patients with the wild-type ITPA genotype (p = 0.033). Furthermore, patients carrying at least one non-functional ITPA allele were shown to be at a lower risk of suffering early (p = 0.003) and/or bone marrow relapse (p = 0.017). In conclusion, the ITPA genotype may serve as a genetic marker for the improvement of risk stratification and therapy individualization for patients with ALL.
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Affiliation(s)
- Alenka Smid
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | | | - Miha Milek
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Janez Jazbec
- University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
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New genetic biomarkers predicting azathioprine blood concentrations in combination therapy with 5-aminosalicylic acid. PLoS One 2014; 9:e95080. [PMID: 24762746 PMCID: PMC3999094 DOI: 10.1371/journal.pone.0095080] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 03/23/2014] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND AND AIMS Azathioprine (AZA) is widely used for the treatment of inflammatory bowel disease (IBD) patients. AZA is catabolized by thiopurine S-methyltransferase (TPMT), which exhibits genetic polymorphisms. It has also been reported that 5-aminosalicylic acid (5-ASA) inhibits TPMT activity, and that increased 6-thioguanine nucleotide (6-TGN, a metabolite of AZA) blood concentrations result in an increased number of ADRs. In this study, single nucleotide polymorphisms (SNPs) related to differential gene expression affecting AZA drug metabolism in combination therapy with 5-ASA were examined. METHODS To identify genetic biomarkers for the prediction of 6-TGN blood concentration, ExpressGenotyping analysis was used. ExpressGenotyping analysis is able to detect critical pharmacogenetic SNPs by analyzing drug-induced expression allelic imbalance (EAI) of premature RNA in HapMap lymphocytes. We collected blood samples on 38 patients with inflammatory bowel disease treated with AZA and corroboration of the obtained SNPs was attempted in clinical samples. RESULTS A large number of SNPs with AZA/5-ASA-induced EAI within the investigated HapMap lymphocytes was identified by ExpressGenotyping analysis. The respective SNPs were analyzed in IBD patients' blood samples. Among these SNPs, several that have not yet been described to be induced by AZA/5-ASA were found. SNPs within SLC38A9 showed a particular correlation with patients' 6-TGN blood concentrations. CONCLUSIONS Based on these results, ExpressGenotyping analysis and genotyping of patients appears to be a useful way to identify inter-individual differences in drug responses and ADRs to AZA/5-ASA. This study provides helpful information on genetic biomarkers for optimized AZA/5-ASA treatment of IBD patients.
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Correlation of thiopurine methyltransferase and inosine triphosphate pyrophosphatase polymorphisms and adverse effects induced by azathioprine treatment in Taiwanese dermatology patients. DERMATOL SIN 2014. [DOI: 10.1016/j.dsi.2013.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Lee MN, Woo HI, Lee YM, Kang B, Kim JW, Choe YH, Lee SY. Successful azathioprine treatment with metabolite monitoring in a pediatric inflammatory bowel disease patient homozygous for TPMT*3C. Yonsei Med J 2013; 54:1545-9. [PMID: 24142665 PMCID: PMC3809851 DOI: 10.3349/ymj.2013.54.6.1545] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Thiopurine S-methyltransferase (TPMT) methylates purine analogues, showing TPMT activity in inverse relation to concentrations of active metabolites such as 6-thioguanine nucleotide (6-TGN). With conventional dosing of thiopurines, patients with homozygous variant TPMT alleles consistently suffer from severe myelosuppression. Here, we report a patient with TPMT*3C/*3C who managed successfully with monitoring of thiopurine metabolites. The patient was an 18-year-old male diagnosed with Crohn's disease. The standard dose of azathioprine (AZA) (1.8 mg/kg/day) with mesalazine (55.6 mg/kg/day) was prescribed. Two weeks after starting AZA treatment, the patient developed leukopenia. The DNA sequence analysis of TPMT identified a homozygous missense variation (NM_000367.2: c.719A>G; p.Tyr240Cys), TPMT*3C/*3C. He was treated with adjusted doses of azathioprine (0.1-0.2 mg/kg/day) and his metabolites were closely monitored. Leukopenia did not reoccur during the follow-up period of 24 months. To our knowledge, this is the first case of a patient homozygous for TPMT*3C successfully treated with azathioprine in Korea. While a TPMT genotyping test may be helpful to determine a safe starting dose, it may not completely prevent myelosuppression. Monitoring metabolites as well as routine laboratory tests can contribute to assessing drug metabolism and optimizing drug dosing with minimized drug-induced toxicity.
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Affiliation(s)
- Mi-Na Lee
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye In Woo
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoo Min Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ben Kang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Won Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo-Youn Lee
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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34
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Roberts RL, Barclay ML. Current relevance of pharmacogenetics in immunomodulation treatment for Crohn's disease. J Gastroenterol Hepatol 2012; 27:1546-54. [PMID: 22741564 DOI: 10.1111/j.1440-1746.2012.07220.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
No drug therapy is completely risk free, and the costs associated with non-response and adverse effects can exceed the cost of the therapy. The ultimate goal of pharmacogenetic research is to find robust genetic predictors of drug response that enable the development of prospective genetic tests to reliably identify patients at risk of non-response or of developing an adverse effect prior to the drug being prescribed. Currently, thiopurine S-methyltransferase (TPMT) deficiency is the only pharmacogenetic factor that is prospectively assessed before azathioprine or 6-mercaptopurine immunomodulation is commenced in patients with Crohn's disease (CD). As yet no other inherited determinant of drug response has made the transition from bench to bedside for the management of this disease. In this review we summarize what is known about TPMT deficiency and explore whether there is evidence to support a role of other genetic polymorphisms in predicting the response of CD patients to thiopurine drugs, methotrexate, and anti-tumor necrosis factor α (TNFα) therapy.
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Affiliation(s)
- Rebecca L Roberts
- Department of Surgical Sciences, Dunedin School of Medicine, Dunedin, New Zealand.
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35
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Azathioprine in the Treatment of Autoimmune Blistering Diseases. Immunol Allergy Clin North Am 2012; 32:295-307, vii-viii. [DOI: 10.1016/j.iac.2012.04.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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36
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Jung YS, Cheon JH, Hong SP, Kim TI, Kim WH. Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet's disease. Inflamm Bowel Dis 2012; 18:750-7. [PMID: 21618352 DOI: 10.1002/ibd.21757] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Accepted: 04/04/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND To date, there have been no studies focusing on the efficacy of thiopurine therapy in intestinal Behcet's disease (BD). We conducted this study to investigate clinical outcomes and predictors of clinical relapse in intestinal BD patients receiving thiopurine maintenance therapy. METHODS We reviewed the medical records of all patients with intestinal BD who received thiopurine therapy in a single tertiary academic medical center between March 1986 and October 2010. The cumulative probabilities of clinical relapse after remission were calculated using the Kaplan-Meier method. Predictors of clinical relapse were identified by univariate analysis using the log-rank test and by multivariate analysis using Cox proportional hazards regression models. RESULTS Of a total of 272 patients with intestinal BD, 67 (24.6%) received their first course of thiopurine therapy at our center. Thirty-nine (58.2%) of the 67 patients constantly received thiopurines for maintaining medically or surgically induced remission. The cumulative relapse rates at 1 year, 2 years, 3 years, and 5 years after remission were 5.8%, 28.7%, 43.7%, and 51.7%, respectively. On multivariate analysis, a younger age (<25 years) at diagnosis and a lower hemoglobin level (<11 g/dL) were independent predictive factors for relapse in intestinal BD patients receiving thiopurine maintenance therapy. CONCLUSIONS Thiopurine therapy showed a relatively good effect for maintenance of remission in intestinal BD patients. However, a younger age at diagnosis and a lower hemoglobin level were associated with a poor response to thiopurines, necessitating early adoption of effective alternative therapeutic options in these risk groups.
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Affiliation(s)
- Yoon Suk Jung
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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37
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Wan Rosalina WR, Teh LK, Mohamad N, Nasir A, Yusoff R, Baba AA, Salleh MZ. Polymorphism of ITPA 94C>A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. J Clin Pharm Ther 2012; 37:237-41. [PMID: 21545474 DOI: 10.1111/j.1365-2710.2011.01272.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA 94C>A) contribute to variable responses, including fatal adverse effects, among subjects treated with 6-mercaptopurine (6-MP). Our objectives were to investigate the distribution of specific TPMT and ITPA genotypes in healthy subjects and patients with acute lymphoblastic leukaemia (ALL) from the three main ethnic groups (Malays, Chinese and Indians) in Malaysia and the association of the polymorphisms with adverse effects of 6-MP. METHODS Patients with ALL and healthy controls were recruited and genotyped for genetic variants of TPMT and ITPA 94C>A. The relationship between genotypes and clinical outcomes was investigated. RESULTS AND DISCUSSION Acute lymphoblastic leukaemia patients with allele ITPA 94A were more likely to develop fever and liver toxicity with 6-MP. The prevalence of TPMT variants was low and this makes it unlikely that testing for them would be useful in our populations. Only patients heterozygous for TPMT*3C were detected. WHAT IS NEW AND CONCLUSION Our results suggest that ITPA 94C>A testing, but not TPMT testing, may help in minimizing the adverse effects of 6-MP in Malaysian patients. However, whether this is true in clinical practice requires a larger study and formal randomized controlled evaluation.
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Affiliation(s)
- W R Wan Rosalina
- Pharmacogenomics Center (PROMISE), Faculty of Pharmacy, Universiti Teknologi MARA, Selangor, Malaysia
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Meggitt SJ, Anstey AV, Mohd Mustapa MF, Reynolds NJ, Wakelin S. British Association of Dermatologists' guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol 2012; 165:711-34. [PMID: 21950502 DOI: 10.1111/j.1365-2133.2011.10575.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- S J Meggitt
- Department of Dermatology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
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Tanaka Y, Manabe A, Nakadate H, Kondoh K, Nakamura K, Koh K, Utano T, Kikuchi A, Komiyama T. The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children. Leuk Res 2011; 36:560-4. [PMID: 22200619 DOI: 10.1016/j.leukres.2011.11.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 10/24/2011] [Accepted: 11/22/2011] [Indexed: 01/29/2023]
Abstract
The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.
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Affiliation(s)
- Yoichi Tanaka
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
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Abstract
Although there are no standard guidelines for the treatment of autoimmune blistering diseases, azathioprine has shown good efficacy in acquired autoimmune blistering diseases, and is well tolerated. Side effects of azathioprine normally occur in mild variants. Severe reactions are due to reduced thiopurine S-methyltransferase (TPMT) or inosine triphosphate pyrophosphohydrolase (ITPA) activity. Therefore, screening for TPMT activity should be conducted in white patients and Africans, whereas Japanese should be screened for ITPA activity before therapy with azathioprine is started. Azathioprine is clinically meaningful for the treatment of pemphigus.
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Affiliation(s)
- Volker Meyer
- Department of Dermatology, University of Muenster, Von-Esmarch-Str. 58, D-48149 Muenster, Germany
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Osaki R, Imaeda H, Ban H, Aomatsu T, Bamba S, Tsujikawa T, Sasaki M, Fujiyama Y, Andoh A. Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease. Exp Ther Med 2011; 2:783-786. [PMID: 22977575 PMCID: PMC3440725 DOI: 10.3892/etm.2011.287] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 06/09/2011] [Indexed: 12/14/2022] Open
Abstract
Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan(®) PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan(®) PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.
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Association Between Adverse Effects Under Azathioprine Therapy and Inosine Triphosphate Pyrophosphatase Activity in Patients With Chronic Inflammatory Bowel Disease. Ther Drug Monit 2011; 33:321-8. [DOI: 10.1097/ftd.0b013e31821a7c34] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Thia KT, Li M, Ling KL, Kong SC, Ooi CJ. Azathioprine is effective in corticosteroid-dependent Asian inflammatory bowel disease patients. Inflamm Bowel Dis 2011; 17:809-15. [PMID: 20645318 DOI: 10.1002/ibd.21382] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Azathioprine (AZA) is widely used to treat corticosteroid (CS)-dependent IBD patients but evidence supporting its use in Asian IBD patients is limited. We evaluated the efficacy of AZA in a single-center cohort of CS-dependent Asian IBD patients. METHODS Patients treated with AZA were identified from our registry and the medical records were reviewed. Inclusion criterion was: first course of AZA and treatment duration ≥ 6 months. Clinical response was assessed at 6 months and classified as complete response, partial response, and nonresponse. Factors associated with response (age, gender, ulcerative colitis [UC] extent, Crohn's disease [CD] behavior, ethnicity, concomitant 5-aminosalicylates/sulfasalazine, baseline activity, disease duration, leukocyte count, mean corpuscular volume, and AZA dose) were analyzed using the chi-square or Mann-Whitney U-test. Probability of sustained remission was estimated using the Kaplan-Meier method. Differences in survival curves between factors were tested with log-rank tests. RESULTS Sixty-four patients were included. At baseline the median age was 37.5 (range, 15-76) years, 50% male, 59.4% Chinese, 50% CD, 50% UC, and mean CS dose 20.2 (SD 10.9) mg. At month 6, complete response was 48.4% (95% confidence interval [CI], 36.7-61.3), partial response 45.1% (95% CI, 32.8-58.3), and nonresponse 7.8% (95% CI, 2.6-17.3). Partial responders had mean CS dose reductions of 11.7 mg (95% CI, 7.2-16.4, P < 0.001). The proportion of patients with sustained remission was 0.87 (95% CI, 0.73-1.0) at 2 years, 0.76 (95% CI, 0.57-0.95) at 3 years, and 0.61 (95% CI, 0.30-0.91) at 5 years of AZA treatment. Female gender was positively associated with sustained remission. CONCLUSIONS Our study demonstrates the short- and long-term effectiveness of AZA therapy among CS-dependent Asian IBD patients.
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Affiliation(s)
- Kelvin T Thia
- Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.
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Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J Clin Gastroenterol 2010; 44:e242-8. [PMID: 20308917 DOI: 10.1097/mcg.0b013e3181d6baf5] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Myelotoxicity has been shown to be very common in Korean patients with inflammatory bowel disease (IBD) during azathioprine (AZA) or 6-mercaptopurine (6-MP) treatment. The purpose of this study was to investigate the relative risk of the thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genotypes and TPMT activity for the development of leukopenia in Korean IBD patients during AZA/6-MP treatment. METHODS We retrospectively analyzed 286 Korean patients with IBD who had been treated with AZA/6-MP for at least 6 months between June 1996 and September 2006. Common TPMT mutations, including TPMT*1, *2, *3A, *3B, and *3C, and ITPA mutations, including 94C>A and IVS2+21A>C, were determined using a high-performance liquid chromatography method. TPMT activity was measured using liquid chromatography with coupled mass spectrometry/mass spectrometry. RESULTS Leukopenia occurred in 118 cases (41.3%). TPMT *1/*3C was detected in 7 cases (2.4%), and ITPA 94 C>A was detected in 66 cases (23.1%), including 63 heterozygotes (22.1%) and 3 homozygotes (1.0%). The median TPMT activity was 9.3 U/mL (interquartile range 10.4, range 2.1 to 76.2). Cox regression analysis revealed that patients with heterozygous *3C type TPMT had a higher probability of leukopenia than those with wild type TPMT (P=0.02). Patients with intermediate TPMT activity had a lower probability of leukopenia than those with low activity (P=0.01). However, the ITPA genotype did not affect the risk of leukopenia. CONCLUSIONS Our data showed that it could be helpful to examine TPMT genotypes and to measure TPMT activity in Korean patients taking AZA/6-MP to predict the development of leukopenia.
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Ohtsuka Y, Arai K, Aoyagi Y, Fujii T, Yamakawa Y, Ohtani K, Ikuse T, Baba Y, Inage E, Kudo T, Suzuki R, Nagata S, Shimizu T. Monitoring 6-thioguanine nucleotide concentrations in Japanese children and adolescents with inflammatory bowel disease. J Gastroenterol Hepatol 2010; 25:1626-30. [PMID: 20880170 DOI: 10.1111/j.1440-1746.2010.06364.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIM 6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported. METHODS This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated. RESULTS Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 10(8) red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) (P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations (r = 0.275, P < 0.002). Two patients experienced leukopenia with alopecia, and four transiently experienced increased serum levels of pancreatic enzymes, although no thiopurine S-methyl transferase mutations were confirmed. CONCLUSION The doses of 6-MP or AZA needed to maintain remission in Japanese children with IBD are lower than those reported in Western countries. However, 6-TGN concentrations in this population are higher than previously reported.
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Affiliation(s)
- Yoshikazu Ohtsuka
- Department of Pediatrics and Adolescent Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
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46
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Ochi H, Maekawa T, Abe H, Hayashida Y, Nakano R, Kubo M, Tsunoda T, Hayes CN, Kumada H, Nakamura Y, Chayama K. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy--a genome-wide study of Japanese HCV virus patients. Gastroenterology 2010; 139:1190-7. [PMID: 20637204 DOI: 10.1053/j.gastro.2010.06.071] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2010] [Revised: 06/16/2010] [Accepted: 06/30/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Ribavirin-induced anemia is one of the major causes of discontinuation and dose reduction during anti-hepatitis C virus therapy. Factors influencing this anemia, especially host genetic factors, are poorly understood. In this study we investigated predictive factors in hepatitis C virus patients treated with combination therapy. METHODS We performed a 2-step genome-wide screening followed by replication analysis and fine-mapping using a total of 923 Japanese hepatitis C virus 1b-infected patients treated with pegylated-interferon plus ribavirin. We also applied logistic regression analysis to search for possible independent associations of clinical parameters and genetic variants with treatment-induced hemoglobin (Hb) decline as well as treatment outcomes. RESULTS We identified a variant, located upstream of the inosine triphosphate pyrophosphatase gene on chromosome 20p13 that is significantly associated with treatment-induced anemia (combined P = 6.0 × 10(-14)). Resequencing and fine-mapping revealed several single nucleotide polymorphisms (SNPs) strongly associated with Hb decline, including the nonsynonymous SNP rs1127354 (P = 3.5 × 10(-44)), which was recently reported for other ethnic groups. Another reported SNP, the splicing variant-related SNP rs7270101, was not polymorphic in the Japanese population. Stratified analysis based on rs1127354 genotype revealed that inosine triphosphate pyrophosphatase expression is not correlated with Hb decline, suggesting that rs1127354 is a direct causal variant in the Japanese population. Multivariate analysis demonstrated that age, baseline Hb, baseline platelet count, and rs1127354 were independently associated with severe anemia (Hb <10 g/dL). CONCLUSIONS A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus-infected Japanese patients.
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Affiliation(s)
- Hidenori Ochi
- Laboratory for Liver Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan
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47
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The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease. J Gastroenterol 2010; 45:1014-21. [PMID: 20393862 DOI: 10.1007/s00535-010-0248-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Accepted: 03/29/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. METHODS Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. RESULTS Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with theMRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype(P = 0.049). Of the 15 patients who experienced leucopenia (<3 x 10⁹/l), 7 patients carried the MRP4 variant.The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03–10.57, P = 0.036). CONCLUSIONS These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.
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Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol 2010; 63:288-95. [PMID: 20354201 DOI: 10.1136/jcp.2009.069252] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs. Patients that due to genetic variation lack this enzyme or have lower levels than normal, can be adversely affected if normal doses of thiopurines are prescribed. The evidence for measuring TPMT prior to starting patients on thiopurine drug therapy has been reviewed and the various approaches to establishing a service considered. Until recently clinical guidelines on the use of the TPMT varied by medical specialty. This has now changed, with clear guidance encouraging clinicians to use the TPMT test prior to starting any patient on thiopurine therapy. The TPMT test is the first pharmacogenomic test that has crossed from research to routine use. Several analytical approaches can be taken to assess TPMT status. The use of phenotyping supported with genotyping on selected samples has emerged as the analytical model that has enabled national referral services to be developed to a high level in the UK. The National Health Service now has access to cost-effective and timely TPMT assay services, with two laboratories undertaking the majority of the work at national level and with several local services developing. There appears to be adequate capacity and an appropriate internal market to ensure that TPMT assay services are commensurate with the clinical demand.
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Affiliation(s)
- L T Ford
- Clinical Biochemistry Department, SWBH NHS Trust, City Hospital, Dudley Road, Birmingham B18 5HQ, UK
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Dong XW, Zheng Q, Zhu MM, Tong JL, Ran ZH. Thiopurine S-methyltransferase polymorphisms and thiopurine toxicity in treatment of inflammatory bowel disease. World J Gastroenterol 2010; 16:3187-95. [PMID: 20593505 PMCID: PMC2896757 DOI: 10.3748/wjg.v16.i25.3187] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the relationship between thiopurine S-methyltransferase (TPMT) polymorphisms and thiopurine-induced adverse drug reactions (ADRs) in inflammatory bowel disease (IBD).
METHODS: Eligible articles that compared the frequency of TPMT polymorphisms among thiopurine-tolerant and -intolerant adult IBD patients were included. Statistical analysis was performed with Review Manager 5.0. Sub-analysis/sensitivity analysis was also performed.
RESULTS: Nine studies that investigated a total of 1309 participants met our inclusion criteria. The incidence of TPMT gene mutation was increased 2.93-fold (95% CI: 1.68-5.09, P = 0.0001) and 5.93-fold (95% CI: 2.96-11.88, P < 0.00001), respectively, in IBD patients with thiopurine-induced overall ADRs and bone marrow toxicity (BMT), compared with controls. The OR for TPMT gene mutation in IBD patients with thiopurine-induced hepatotoxicity and pancreatitis was 1.51 (95% CI: 0.54-4.19, P = 0.43) and 1.02 (95% CI: 0.26-3.99, P = 0.98) vs controls, respectively.
CONCLUSION: This meta-analysis suggests that the TPMT polymorphisms are associated with thiopurine-induced overall ADRs and BMT, but not with hepatotoxicity and pancreatitis.
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Yamamoto K, Okada Y, Nakamura K, Hiromura K, Nojima Y, Nakamura T. Inosine triphosphate pyrophosphatase 94C> A polymorphism: clinical implications for patients with systemic lupus erythematosus treated with azathioprine. Expert Opin Drug Saf 2010; 9:447-57. [DOI: 10.1517/14740330903544474] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Koujirou Yamamoto
- Gunma University Graduate School of Medicine, Department of Clinical Pharmacology, 3-39-22 Showa-machi, Maebashi, Gunma 371-0034, Japan ;
| | - Yuko Okada
- Gunma University Graduate School of Medicine, Department of Clinical Pharmacology, 3-39-22 Showa-machi, Maebashi, Gunma 371-0034, Japan ;
| | - Katsunori Nakamura
- Gunma University Graduate School of Medicine, Department of Clinical Pharmacology, 3-39-22 Showa-machi, Maebashi, Gunma 371-0034, Japan ;
| | - Keiju Hiromura
- Gunma University Graduate School of Medicine, Department of Medicine and Clinical Science, Gunma, Japan
| | - Yoshihisa Nojima
- Gunma University Graduate School of Medicine, Department of Medicine and Clinical Science, Gunma, Japan
| | - Tomonori Nakamura
- Gunma University Graduate School of Medicine, Department of Clinical Pharmacology, 3-39-22 Showa-machi, Maebashi, Gunma 371-0034, Japan ;
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