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1
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Deben DS, Derijks LJJ, van den Bosch BJC, Creemers RH, van Nunen A, van Bodegraven AA, Wong DR. Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency. Metabolites 2023; 13:1054. [PMID: 37887379 PMCID: PMC10608562 DOI: 10.3390/metabo13101054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/28/2023] Open
Abstract
Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016-2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.
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Affiliation(s)
- Debbie S. Deben
- Department of Clinical Pharmacy, Clinical Pharmacology and Toxicology, Zuyderland Medical Centre, 6162 BG Sittard, The Netherlands;
| | - Luc J. J. Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Centre, 5504 DB Veldhoven, The Netherlands
| | - Bianca J. C. van den Bosch
- Department of Clinical Genetics, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands
| | - Rob H. Creemers
- Department of Gastroenterology, Zuyderland Medical Centre, 6162 BG Sittard, The Netherlands
- Department of Gastro-Enterology, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands
| | - Annick van Nunen
- Department of Gastroenterology, Zuyderland Medical Centre, 6162 BG Sittard, The Netherlands
| | - Adriaan A. van Bodegraven
- Department of Gastroenterology, Zuyderland Medical Centre, 6162 BG Sittard, The Netherlands
- Department of Gastro-Enterology, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands
| | - Dennis R. Wong
- Department of Clinical Pharmacy, Clinical Pharmacology and Toxicology, Zuyderland Medical Centre, 6162 BG Sittard, The Netherlands;
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2
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Patterson CM, Jolly EC, Burrows F, Ronan NJ, Lyster H. Conventional and Novel Approaches to Immunosuppression in Lung Transplantation. Clin Chest Med 2023; 44:121-136. [PMID: 36774159 DOI: 10.1016/j.ccm.2022.10.009] [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: 02/11/2023]
Abstract
Most therapeutic advances in immunosuppression have occurred over the past few decades. Although modern strategies have been effective in reducing acute cellular rejection, excess immunosuppression comes at the price of toxicity, opportunistic infection, and malignancy. As our understanding of the immune system and allograft rejection becomes more nuanced, there is an opportunity to evolve immunosuppression protocols to optimize longer term outcomes while mitigating the deleterious effects of traditional protocols.
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Affiliation(s)
- Caroline M Patterson
- Transplant Continuing Care Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Elaine C Jolly
- Division of Renal Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Fay Burrows
- Department of Pharmacy, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - Nicola J Ronan
- Transplant Continuing Care Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Haifa Lyster
- Cardiothoracic Transplant Unit, Royal Brompton and Harefield Hospitals, Part of Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom; Kings College, London, United Kingdom; Pharmacy Department, Royal Brompton and Harefield Hospitals, Part of Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.
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3
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Freitas M, Lima Capela T, Macedo Silva V, Arieira C, Cúrdia Gonçalves T, Dias de Castro F, Moreira MJ, Firmino-Machado J, Cotter J. Finding Predictors of Azathioprine-Induced Pancreatitis in Patients With Inflammatory Bowel Disease. Pancreas 2022; 51:288-294. [PMID: 35584388 DOI: 10.1097/mpa.0000000000002012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Azathioprine (AZA)-induced pancreatitis (AIP) is a common, idiosyncratic adverse effect whose incidence and risk factors data in inflammatory bowel disease (IBD) patients are not fully clarified. We aimed to establish the incidence, clinical course and identify risk factors for AIP. METHODS A retrospective study including all IBD patients on AZA between January 2013 and July 2020 was conducted. Patients with AIP were considered. RESULTS Azathioprine-induced pancreatitis occurred in 33 patients (7.5%; 442 patients on AZA). The mean time receiving AZA until AIP was 25 days, with a mean dose of 88 mg. All patients had a mild course of disease, which resolved with suspension of AZA and with no complications. Smoking (P = 0.02), single daily dose of AZA (P < 0.001), and concomitant budesonide (P = 0.001) were risk factors for AIP. In multivariate analysis, concomitant treatment with budesonide (odds ratio, 5.3; P = 0.002) and single daily dose of AZA (odds ratio, 3.8; P = 0.002) were the only predictors of AIP. CONCLUSIONS Although AIP was a relatively common adverse effect, it presented a mild course in all patients. Smoking, concomitant use of budesonide, and single-dose regimen of AZA should be avoided in IBD patients treated with AZA.
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4
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Deben DS, Wong DR, van Bodegraven AA. Current status and future perspectives on the use of therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2022; 17:1433-1444. [PMID: 35023443 DOI: 10.1080/17425255.2021.2029406] [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] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Despite new treatment options for inflammatory bowel disease (IBD), conventional thiopurines remain a common treatment option for maintaining remission, particularly in non-Westernized countries. Therapeutic drug monitoring (TDM) is advised in standard care for optimizing therapy strategies to improve effectiveness, reveal nonadherence and reduce toxicity. Still, the rationale of TDM is debated. AREAS COVERED Key insights on TDM of thiopurine metabolites are discussed. The pharmacology of thiopurines is described, emphasizing the interindividual differences in pharmacogenetics, pharmacokinetics and pharmacodynamics. Pharmacological differences between conventional thiopurines and tioguanine are outlined. Finally, several optimization strategies for thiopurine therapy in IBD are discussed. EXPERT OPINION TDM has been a useful, but limited, tool to individualize thiopurine therapy. Pharmacokinetic data on the active thiopurine metabolites, derived from measurements in erythrocytes, associated with clinical response only partially predict effectiveness and toxicity. An additional pharmacodynamic marker, such as Rac1/pSTAT3 expression in leukocytes, may improve applicability of TDM in the future.
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Affiliation(s)
- Debbie S Deben
- Dept. of Clinical Pharmacy, Clinical pharmacology and Toxicology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands
| | - Dennis R Wong
- Dept. of Clinical Pharmacy, Clinical pharmacology and Toxicology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands
| | - Adriaan A van Bodegraven
- Dept. of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Centre Sittard-Geleen/Heerlen, The Netherlands.,Dept. of Gastroenterology and Hepatology, Amsterdam, The Netherlands
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5
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Franca R, Braidotti S, Stocco G, Decorti G. Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies. Expert Opin Drug Metab Toxicol 2021; 17:1187-1198. [PMID: 34452592 DOI: 10.1080/17425255.2021.1974398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/26/2021] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response. AREAS COVERED This review gives an overview on TPMT gene and function, and discusses the pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB. EXPERT OPINION To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive TPMT genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes and novel individualized TG regimens in maintenance for TPMT wild-type subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.
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Affiliation(s)
- R Franca
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - S Braidotti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - G Stocco
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - G Decorti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
- Institute for Maternal & Child Health (I.r.c.c.s) Burlo Garofolo, Trieste, Italy
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6
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Lin YS, Thummel KE, Thompson BD, Totah RA, Cho CW. Sources of Interindividual Variability. Methods Mol Biol 2021; 2342:481-550. [PMID: 34272705 DOI: 10.1007/978-1-0716-1554-6_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in others. A significant source of this variability in drug response is drug metabolism, where differences in presystemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, Cmax, and/or Cmin) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is recognized that both intrinsic factors (e.g., genetics, age, sex, and disease states) and extrinsic factors (e.g., diet , chemical exposures from the environment, and the microbiome) play a significant role. For drug-metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, upregulation and downregulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less predictable and time-dependent manner. Understanding the mechanistic basis for variability in drug disposition and response is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that will improve outcomes in maintaining health and treating disease.
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Affiliation(s)
- Yvonne S Lin
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
| | - Kenneth E Thummel
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Brice D Thompson
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Rheem A Totah
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
| | - Christi W Cho
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
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7
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Chansavang A, Maalej S, Narjoz C, Loriot MA, Pallet N. Identification of rare defective allelic variants in cases of thiopurine S-methyltransferase deficient activity. Pharmacogenomics 2020; 21:1217-1226. [PMID: 33118454 DOI: 10.2217/pgs-2020-0124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Aim: To assess rare TPMT variants in patients carrying a deficient phenotype not predicted by the four more frequent genotypes (*2, *3A, *3B and *3C). Materials & methods: Next-generation sequencing of TPMT in 39 patients with a discordant genotype. Results: None of the variants identified explained the discordances assuming that they are of uncertain significance according to the Clinical Pharmacogenetics Implementation Consortium classification. Two unknown variants were detected and predicted to result in a splicing defect. We show that TPMT*16 and TMPT*21 are defective alleles, and TPMT*8 and TPMT*24 are associated with a normal activity. Conclusion: Whole-exon sequencing for rare TPMT mutations has a low diagnostic yield. A reassessment of the functional impact of rare variants of uncertain significance is a critical issue.
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Affiliation(s)
- Albain Chansavang
- Service de Biochimie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France
| | - Sadok Maalej
- Service de Biochimie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France
| | - Céline Narjoz
- Service de Biochimie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France
| | - Marie-Anne Loriot
- Service de Biochimie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France.,Université de Paris, INSERM U1138, Centre de Recherche des Cordeliers, F-75006, Paris, France
| | - Nicolas Pallet
- Service de Biochimie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France.,Université de Paris, INSERM U1138, Centre de Recherche des Cordeliers, F-75006, Paris, France
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8
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Harmand PO, Solassol J. Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT. Genes (Basel) 2020; 11:genes11101212. [PMID: 33081236 PMCID: PMC7602704 DOI: 10.3390/genes11101212] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.
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Affiliation(s)
- Pierre-Olivier Harmand
- Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France;
| | - Jérôme Solassol
- Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France;
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, 34298 Montpellier, France
- Correspondence: ; Tel.: + 33-4673-358-71
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9
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Daniel LL, Dickson AL, Chung CP. Precision medicine for rheumatologists: lessons from the pharmacogenomics of azathioprine. Clin Rheumatol 2020; 40:65-73. [PMID: 32617765 DOI: 10.1007/s10067-020-05258-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/16/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022]
Abstract
Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.
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Affiliation(s)
- Laura L Daniel
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA
| | - Alyson L Dickson
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA
| | - Cecilia P Chung
- Department of Medicine, Division of Rheumatology, Vanderbilt University Medical Center (LLD, ALD, CPC), Nashville, TN, 37232, USA. .,Tennessee Valley Healthcare System-Nashville Campus (CPC), Nashville, TN, USA. .,Vanderbilt Genetics Institute, Vanderbilt University School of Medicine (CPC), Nashville, TN, USA.
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10
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Ariffin H, Ab Rahman S, Leong SH, Chiew EKH, Lin HP, Quah TC, Yeoh AEJ. Malaysia-Singapore (MASPORE) leukaemia study group: From common history to successful collaboration. PEDIATRIC HEMATOLOGY ONCOLOGY JOURNAL 2020. [DOI: 10.1016/j.phoj.2020.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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11
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Gibson J, Russ TC, Clarke TK, Howard DM, Hillary RF, Evans KL, Walker RM, Bermingham ML, Morris SW, Campbell A, Hayward C, Murray AD, Porteous DJ, Horvath S, Lu AT, McIntosh AM, Whalley HC, Marioni RE. A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genet 2019; 15:e1008104. [PMID: 31738745 PMCID: PMC6886870 DOI: 10.1371/journal.pgen.1008104 10.1371/journal.pgen.1008104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 12/02/2019] [Accepted: 08/16/2019] [Indexed: 12/20/2023] Open
Abstract
'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.
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Affiliation(s)
- Jude Gibson
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Tom C. Russ
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Dementia Prevention, University of Edinburgh, Edinburgh, United Kingdom
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
| | - Toni-Kim Clarke
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - David M. Howard
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Robert F. Hillary
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Kathryn L. Evans
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Rosie M. Walker
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Mairead L. Bermingham
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stewart W. Morris
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
- Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
| | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Alison D. Murray
- Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, United Kingdom
| | - David J. Porteous
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, United States of America
- Department of Biostatistics, School of Public Health, University of California-Los Angeles, Los Angeles, CA, United States of America
| | - Ake T. Lu
- Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, United States of America
| | - Andrew M. McIntosh
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
| | - Heather C. Whalley
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Riccardo E. Marioni
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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12
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Gibson J, Russ TC, Clarke TK, Howard DM, Hillary RF, Evans KL, Walker RM, Bermingham ML, Morris SW, Campbell A, Hayward C, Murray AD, Porteous DJ, Horvath S, Lu AT, McIntosh AM, Whalley HC, Marioni RE. A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genet 2019; 15:e1008104. [PMID: 31738745 PMCID: PMC6886870 DOI: 10.1371/journal.pgen.1008104] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 12/02/2019] [Accepted: 08/16/2019] [Indexed: 12/22/2022] Open
Abstract
'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.
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Affiliation(s)
- Jude Gibson
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Tom C. Russ
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Dementia Prevention, University of Edinburgh, Edinburgh, United Kingdom
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
| | - Toni-Kim Clarke
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - David M. Howard
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Robert F. Hillary
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Kathryn L. Evans
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Rosie M. Walker
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Mairead L. Bermingham
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stewart W. Morris
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
- Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
| | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Alison D. Murray
- Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, United Kingdom
| | - David J. Porteous
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, United States of America
- Department of Biostatistics, School of Public Health, University of California-Los Angeles, Los Angeles, CA, United States of America
| | - Ake T. Lu
- Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, United States of America
| | - Andrew M. McIntosh
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
| | - Heather C. Whalley
- Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Riccardo E. Marioni
- Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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13
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Derijks LJJ, Wong DR, Hommes DW, van Bodegraven AA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease. Clin Pharmacokinet 2019; 57:1075-1106. [PMID: 29512050 DOI: 10.1007/s40262-018-0639-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.
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Affiliation(s)
- Luc J J Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Center, PO Box 7777, 5500 MB, Veldhoven, The Netherlands.
| | - Dennis R Wong
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Daniel W Hommes
- Center for Inflammatory Bowel Diseases, UCLA, Los Angeles, CA, USA
| | - Adriaan A van Bodegraven
- Department of Gastroenterology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
- Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands
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14
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Zarca K, Durand-Zaleski I, Loriot MA, Chatellier G, Pallet N. Modeling the Outcome of Systematic TPMT Genotyping or Phenotyping Before Azathioprine Prescription: A Cost-Effectiveness Analysis. Mol Diagn Ther 2019; 23:429-438. [PMID: 30963516 DOI: 10.1007/s40291-019-00398-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Thiopurine S-methyltransferase (TPMT) testing, either by genotyping or phenotyping, can reduce the incidence of adverse severe myelotoxicity episodes induced by azathioprine. The comparative cost-effectiveness of TPMT genotyping and phenotyping are not known. OBJECTIVE Our aim was to assess the cost-effectiveness of phenotyping-based dosing of TPMT activity, genotyping-based screening and no screening (reference) for patients treated with azathioprine. METHODS A decision tree was built to compare the conventional weight-based dosing strategy with phenotyping and with genotyping using a micro-simulation model of patients with inflammatory bowel disease from the perspective of the French health care system. The time horizon was set up as 1 year. Only direct medical costs were used. Data used were obtained from previous reports, except for screening test and admission costs, which were from real cases. The main outcome was the cost-effectiveness ratios, with an effectiveness criterion of one averted severe myelotoxicity episode. RESULTS The total expected cost of the no screening strategy was €409/patient, the total expected cost of the phenotyping strategy was €427/patient, and the total expected cost of the genotyping strategy was €476/patient. The incremental cost-effectiveness ratio was €2602/severe myelotoxicity averted in using the phenotyping strategy, and €11,244/severe myelotoxicity averted in the genotyping strategy compared to the no screening strategy. At prevalence rates of severe myelotoxicity > 1%, phenotyping dominated genotyping and conventional strategies. CONCLUSION The phenotype-based strategy to screen for TPMT deficiency dominates (cheaper and more effective) the genotype-based screening strategy in France. Phenotype-based screening dominates no screening in populations with a prevalence of severe myelosuppression due to azathioprine of > 1%.
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Affiliation(s)
- Kevin Zarca
- Assistance Publique-Hôpitaux de Paris, DRCI-URC Eco Ile-de-France (AP-HP), Paris, France.,Assistance Publique-Hôpitaux de Paris, service de santé publique, Henri Mondor-Albert-Chenevier, Créteil, France
| | - Isabelle Durand-Zaleski
- Assistance Publique-Hôpitaux de Paris, DRCI-URC Eco Ile-de-France (AP-HP), Paris, France.,Assistance Publique-Hôpitaux de Paris, service de santé publique, Henri Mondor-Albert-Chenevier, Créteil, France
| | - Marie-Anne Loriot
- Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descates, 20, rue Leblanc, 75015, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Gilles Chatellier
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Unité de Recherche Clinique, Paris, France.,Centre d'Investigation Clinique 1418 (CIC1418), Paris, France
| | - Nicolas Pallet
- Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descates, 20, rue Leblanc, 75015, Paris, France. .,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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15
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Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, Zhang Y, Hou Q, Yang X, Wang H, Ma Z, Wang H, Zhu Y, Zhang W, Wang Y, Liu B, Wang L, Xu H, Shu Y. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. Oncotarget 2017; 8:13575-13585. [PMID: 28088792 PMCID: PMC5355121 DOI: 10.18632/oncotarget.14594] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/04/2017] [Indexed: 02/05/2023] Open
Abstract
Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13–10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.
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Affiliation(s)
- Dandan Yin
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xuyang Xia
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junlong Zhang
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shouyue Zhang
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fei Liao
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ge Zhang
- Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China
| | - Yan Zhang
- Department of Thoracic Oncology, Cancer Center, National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qianqian Hou
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xue Yang
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Hong Wang
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Zhigui Ma
- Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China
| | - Heyao Wang
- Department of Precision Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Yiping Zhu
- Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China
| | - Yuelan Wang
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bo Liu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lanlan Wang
- Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Heng Xu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Shu
- Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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16
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Pharmacogénétique des immunosuppresseurs : état des connaissances et des pratiques – recommandations du Réseau national de pharmacogénétique (RNPGx). Therapie 2017; 72:269-284. [DOI: 10.1016/j.therap.2016.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022]
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17
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Woillard JB, Chouchana L, Picard N, Loriot MA. Pharmacogenetics of immunosuppressants: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics (RNPGx). Therapie 2017; 72:285-299. [PMID: 28318610 DOI: 10.1016/j.therap.2016.09.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/02/2016] [Indexed: 12/21/2022]
Abstract
Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of (i) immunosuppressive drugs used in transplantation and (ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use of currently available major pharmacogenetic tests are detailed and recommendations are provided based on a scale established by the RNPGx scoring tests as "essential", "advisable" and "potentially useful". Other applications for which the level of evidence is still debated are also discussed.
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Affiliation(s)
- Jean-Baptiste Woillard
- Service de pharmacologie, toxicologie et pharmacovigilance, centre de biologie et de recherche en santé, CHU de Limoges, 87042 Limoges, France; Université de Limoges UMR_S850, 87000 Limoges, France.
| | - Laurent Chouchana
- Service de pharmacologie, hôpital Cochin, Assistance publique-Hôpitaux de Paris (AP-HP), 75014 Paris, France
| | - Nicolas Picard
- Service de pharmacologie, toxicologie et pharmacovigilance, centre de biologie et de recherche en santé, CHU de Limoges, 87042 Limoges, France; Université de Limoges UMR_S850, 87000 Limoges, France
| | - Marie-Anne Loriot
- Inserm UMR_S1147, centre universitaire des Saints-Pères, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Service de biochimie, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France
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18
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Traditional Chinese medicine combination therapy for patients with steroid-dependent ulcerative colitis: study protocol for a randomized controlled trial. Trials 2017; 18:8. [PMID: 28069051 PMCID: PMC5223474 DOI: 10.1186/s13063-016-1763-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 12/18/2016] [Indexed: 02/08/2023] Open
Abstract
Background Approximately 20% of patients with ulcerative colitis become steroid dependent. Azathioprine is recommended in steroid-dependent ulcerative colitis, but its side effects limit its use. Chinese herbal medicine has been widely used to treat ulcerative colitis in China. However, its effectiveness in steroid-dependent patients has not been evaluated. This study aims to investigate the efficacy of traditional Chinese medicine combination therapy with 5-aminosalicylic acid in patients with steroid-dependent ulcerative colitis. Methods/Design This is a parallel, multicenter, randomized controlled trial. One hundred and twenty eligible patients will be randomly assigned to a traditional Chinese medicine group or azathioprine group. All patients will be given basic treatment, which includes steroids and 5-aminosalicylic acid. Patients allocated to the traditional Chinese medicine group will receive basic treatment plus Chinese herbal medicine granules, while patients in the azathioprine group will receive basic treatment plus azathioprine. The whole study will last 24 weeks. The primary outcome measure is the steroid-free remission rate. Secondary outcome measures are health-related quality of life, efficacy of endoscopic response, degree of mucosal healing, and inflammation indicators. Discussion Results from this study may provide evidence for the effectiveness of traditional Chinese medicine combined with 5-aminosalicylic acid in patients with steroid-dependent ulcerative colitis. The findings will provide a basis for further confirmatory studies. Trial registration Chinese Clinical Trial Register, ChiCTR-IPR-15005760. Registered on 2 January 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1763-9) contains supplementary material, which is available to authorized users.
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19
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Daenen SM, De Wolf JT, Vellenga E, Van Imhoff GW, Smit JW, Berg-De Rutter EVD. 6-Mercaptopurine, Still Valuable for the Palliative Treatment of Acute Myeloid Leukaemia. Hematology 2016; 6:231-40. [DOI: 10.1080/10245332.2001.11746576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Simon M.G.J. Daenen
- Department of Haematolog, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Joost Th.M. De Wolf
- Department of Haematolog, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Edo Vellenga
- Department of Haematolog, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Gustaaf W. Van Imhoff
- Department of Haematolog, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Jan W. Smit
- Central Laboratory, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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20
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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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21
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Fangbin Z, Xiang G, Liang D, Hui L, Xueding W, Baili C, Huichang B, Yinglian X, Peng C, Lizi Z, Yanjun C, Feng X, Minhu C, Min H, Pinjin H. Prospective Evaluation of Pharmacogenomics and Metabolite Measurements upon Azathioprine Therapy in Inflammatory Bowel Disease: An Observational Study. Medicine (Baltimore) 2016; 95:e3326. [PMID: 27082580 PMCID: PMC4839824 DOI: 10.1097/md.0000000000003326] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Up to approximately 40% to 50% of patients discontinue thiopurine therapy during the course of inflammatory bowel disease (IBD). We investigated the role of the metabolite thiopurine in IBD treatment. This was a prospective study. IBD patients receiving azathioprine (AZA) were prospectively included. Thiopurine methyltransferase (TPMT) genotypes were examined before therapy, and thiopurine metabolite levels were examined at weeks 2, 4, 8, 12, 24, and 48. In total, 132 patients were included. The frequency of leucopenia increased at 6-thioguanine nucleotide (6-TGN) levels ≥420 pmol/8 × 10(8) RBC (odds ratio [OR] = 7.9; 95% confidence interval (95%CI): 3.5-18.0; P < 0.001) and increased more during the initial 12 weeks of thiopurine therapy (OR = 16.0; 95%CI: 5.7-44.9; P < 0.001). The patients with 6-TGN levels ≥420 pmol/8 × 10 RBC at weeks 4, 8, and 12 had an increased likelihood of leucopenia. Clinical response increased at 6-TGN levels ≥225 pmol/8 × 10(8) RBC (OR = 13.5; 95% CI: 3.7-48.9; P < 0.001) in Crohn disease (CD) patients. The CD patients with 6-TGN levels ≥225 pmol/8 × 10(8) RBC at weeks 8, 12, and 24 had an increased likelihood of successful clinical response. TPMT*3C had a specificity of 100%, but a sensitivity of 8% for predicting leucopenia.A 6-TGN level between 225 and 420 pmol/8 × 10(8) RBC could be a therapeutic window in patients receiving AZA therapy, and it could likely predict leucopenia in the initial 12 weeks of AZA therapy and a reasonable chance of successful clinical response in CD patients. The value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia.
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Affiliation(s)
- Zhang Fangbin
- From the Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou (ZF, CP, CY, XF); Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-sen University (ZF, GX, CB, XY, CM, HP); Department of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University (GX, HP); Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (DL, LH, WX, BH, ZL, HM); and Department of Pharmacology, the First Affiliated Hospital of Jinan University (LH), Guangzhou, China)
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22
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Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment. Eur J Clin Pharmacol 2015; 71:773-99. [PMID: 26008212 DOI: 10.1007/s00228-015-1862-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/04/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism. RESULTS It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics.
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23
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Zeglam HB, Benhamer A, Aboud A, Rtemi H, Mattardi M, Saleh SS, Bashein A, Enattah N. Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population. Libyan J Med 2015; 10:27053. [PMID: 25819542 PMCID: PMC4376936 DOI: 10.3402/ljm.v10.27053] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Accepted: 03/02/2015] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile. METHODS We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G>C, *3A (c.460 G>A and c.719 A>G), *3B (c.460 G>A), and *3C (c.719 A>G). RESULTS Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL. CONCLUSIONS We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression.
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Affiliation(s)
- Hamza Ben Zeglam
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya
| | - Abdrazak Benhamer
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya
| | - Adel Aboud
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya
| | - Haitem Rtemi
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya
| | - Meftah Mattardi
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya
| | - Saleh Suleiman Saleh
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya
| | - Abdullah Bashein
- Department of Biochemistry, Faculty of Medicine, University of Tripoli, Tripoli, Libya
| | - Nabil Enattah
- Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya; ;
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Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine. Int J Mol Sci 2015; 16:4281-305. [PMID: 25690039 PMCID: PMC4346957 DOI: 10.3390/ijms16024281] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/04/2015] [Accepted: 02/09/2015] [Indexed: 12/25/2022] Open
Abstract
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.
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Belen BF, Gürsel T, Akyürek N, Albayrak M, Kaya Z, Koçak Ü. Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy. Turk J Haematol 2014; 31:276-85. [PMID: 25541649 PMCID: PMC4454056 DOI: 10.4274/tjh.2013.0082] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C.
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Affiliation(s)
- Burcu Fatma Belen
- Gazi University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey. E-ma-il:
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Should thiopurine methyltransferase genotypes and phenotypes be measured before thiopurine therapy in patients with inflammatory bowel disease? Ther Drug Monit 2013; 34:695-701. [PMID: 23149442 DOI: 10.1097/ftd.0b013e3182731925] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS Not all of the adverse effects to thiopurine therapy can be explained by thiopurine methyltransferase (TPMT) polymorphisms. This study was intended to evaluate the value of TPMT genotype and phenotype measurement during the first year of thiopurine therapy. METHODS Consecutive patients with inflammatory bowel disease (IBD) who were receiving azathioprine or 6-mercaptopurine were followed up for 12 months. TPMT genotypes and phenotypes were examined in patients with IBD before thiopurine therapy and in unrelated healthy volunteers by polymerase chain reaction and high-performance liquid chromatography. RESULTS A total of 199 patients and 300 healthy volunteers were included at 2 centers. Forty-seven of the 199 patients (23.62%) exhibited adverse effects during the entire course of thiopurine therapy. Two (1%) patients carrying TPMT*3C developed leucopenia at week 4 of azathioprine treatment. The TPMT*3C had a specificity of 100% (163/163) but a sensitivity of 5.56% (2/36) for predicting leucopenia. The calculated optimal cutoff activity for high TPMT activity and decreased TPMT activity was 4.75 U/mL red blood cells. The risk of leucopenia increased in the decreased TPMT group (odds ratio: 20.25; 95% confidence interval: 2.19-187.17; P = 0.004) and increased more during the initial 3 months of thiopurine therapy (odds ratio: 34.80; 95% confidence interval: 3.71-326.77; P = 0.001). Leucopenia occurred more frequently in the patients cotreated with 5-aminosalicylates than in those not cotreated (32.81% versus 11.11%, respectively, P < 0.001). CONCLUSIONS The results of this study suggest that the value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia, and that phenotyping is a more cost-effective tool that can be successfully used in patients. The coadministration of 5-aminosalicylates results in a high frequency of leucopenia in patients receiving azathioprine or 6-mercaptopurine.
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Zabala W, Cruz R, Barreiro-de Acosta M, Chaparro M, Panes J, Echarri A, Esteve M, Carpio D, Andreu M, García-Planella E, Domenech E, Carracedo A, Gisbert JP, Barros F. New genetic associations in thiopurine-related bone marrow toxicity among inflammatory bowel disease patients. Pharmacogenomics 2013; 14:631-40. [DOI: 10.2217/pgs.13.38] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: The toxicity related to thiopurine drug therapy for inflammatory bowel disease (IBD) varies widely among patients. Almost 15–30% of patients with IBD develop side effects during treatment, often bone marrow suppression. Several factors have been implicated in determining this toxicity, mainly individual genetic variation related to formation of active thiopurine metabolites. The aim was to identify genes involved in thiopurine-related myelosuppression. Materials & methods: A two-stage investigation of 19,217 coding SNPs (cSNPs) was performed in a Spanish (Inflammatory Bowel Disease Group of Galicia [EIGA]) cohort of 173 IBD patients, 15 with bone marrow suppression. The top 20 cSNPs identified in the first stage with p < 10-3 for allelic test association and SNPs that define the common TPMT alleles were replicated in a different Spanish (ENEIDA) cohort (87 patients, 29 with bone marrow suppression). Results: Several cSNPs showed a significant p-value in the allelic joint analysis (p-Cochran–Mantel–Haenszel test ≤2.55 × 10-3) despite no cSNP passing correction for multiple testing in the first cohort. Of note is rs3729961 in the gene IL6ST, a transducer signal chain shared by many cytokines including IL6 (p-value combined = 2.36 × 10-4, odds ratio [95% CI]: 3.41 [1.71–6.78]). In addition, we detected association with rs3749598 in the FSTL5 gene that appears to interact with metalloproteases at the extracellular matrix level (p-value combined = 4.89 × 10-4), odds ratio (95% CI): 3.67 (1.68–8.01). Conclusion: We have identified IL6ST and FSLT5 as new bone marrow suppression susceptibility candidate genes after thiopurine treatment in IBD patients. This is the first report of variants associated with thiopurine-related myelosuppression that was identified by a genome-wide association study. Its validation awaits functional analyses and replication in additional studies. Original submitted 14 September 2012; Revision submitted 13 February 2013
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Affiliation(s)
- William Zabala
- Fundación Pública Galega de Medicina Xenómica – SERGAS, Santiago de Compostela, Spain and Instituto de Investigaciones Genéticas, Facultad de Medicina, Universidad Del Zulia, Venezuela
| | - Raquel Cruz
- CIBERER – USC, Santiago de Compostela, Spain
| | | | - María Chaparro
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP) & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | | | - Maria Esteve
- Hospital Mutua de Terrassa & CIBEREHD, Terrassa, Spain
| | - Daniel Carpio
- Complexo Hospitalario de Pontevedra, Pontevedra, Spain
| | | | | | | | - Angel Carracedo
- Fundación Pública Galega de Medicina Xenómica – SERGAS, Santiago de Compostela, Spain and CIBERER – USC, Santiago de Compostela, Spain
| | - Javier P Gisbert
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP) & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Francisco Barros
- Fundación Publica Galega de Medicina Xenómica, Hospital Clinico Universitario, 15706, Santiago de Compostela, Spain and CIBERER – USC, Santiago de Compostela, Spain
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Polymorphism of genes involved in purine metabolism (XDH, AOX1, MOCOS) in kidney transplant recipients receiving azathioprine. Ther Drug Monit 2013; 34:266-74. [PMID: 22495427 DOI: 10.1097/ftd.0b013e31824aa681] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Xanthine dehydrogenase (XDH), aldehyde oxidase1 (AOX1), and molybdenum cofactor sulfurase (MOCOS) are enzymes involved in purine metabolism. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in XDH, AOX1, and MOCOS genes in relation to clinical parameters and risk of drug side effects in a cohort of kidney transplant recipients treated with azathioprine (AZA) as a part of standard immunosuppressive regimen. METHODS One hundred fifty-six patients receiving AZA for the first year from the surgery were genotyped for the presence of common SNPs in the coding regions of XDH, AOX1, and MOCOS genes using TaqMan assays. RESULTS AOX1 rs55754655 variant allele carriers received a higher mean AZA dose 3, 6, and 12 months after transplantation (P < 0.05). The patients inheriting rs594445 MOCOS minor allele required significantly lower doses of AZA for efficient treatment compared with wild-type heterozygotes at 3, 6, and 12 months from the transplantation (mean values: 1.39 versus 1.59, 1.38 versus 1.58, and 1.33 versus 1.53 mg·kg·24 h) and displayed lower mean RBC count at the time points evaluated. Multivariate analysis has shown that the effect of MOCOS rs594445 polymorphism is independent of other investigated gene variations and might influence AZA dosage, similarly to TPMT heterozygosity. The authors have not observed an association between any of the studied XDH SNPs and clinical parameters of AZA-treated patients. CONCLUSIONS The results of this study should be regarded as preliminary. However, if the observed association between SNPs: AOX1 rs55754655, MOCOS rs594445, and AZA dose requirements would be positively confirmed in further independent studies, it could be introduced into clinical practice to individualize thiopurine treatment.
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Gilissen LPL, Wong DR, Engels LGJB, Bierau J, Bakker JA, Paulussen ADC, Romberg-Camps MJ, Stronkhorst A, Bus P, Bos LP, Hooymans PM, Stockbrügger RW, Neef C, Masclee AAM. Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy. J Crohns Colitis 2012; 6:698-707. [PMID: 22398098 DOI: 10.1016/j.crohns.2011.12.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Revised: 11/28/2011] [Accepted: 12/05/2011] [Indexed: 01/07/2023]
Abstract
BACKGROUND AND AIMS Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥235 pmol/8×10(8) erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level. METHODS Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity. RESULTS Forty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8×10(8) erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8×10(8) erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04). CONCLUSIONS Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response.
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Affiliation(s)
- Lennard P L Gilissen
- Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, The Netherlands.
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Thiopurine methyltransferase genotype and thiopurine S-methyltransferase activity in Greek children with inflammatory bowel disease. Ann Gastroenterol 2012. [PMID: 24714152 DOI: 10.1016/s1873-9946(12)60248-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Azathioprine (AZA) and 6-mercaptopurine (6MP) are used in the treatment of pediatric inflammatory bowel disease (IBD). Genetic variations in thiopurine S-methyltranfarase (TPMT) gene have been correlated with enzyme activity and with the occurrence of adverse events to AZA and 6MP. The aim of the present study was to examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in children with IBD. METHODS TPMT red blood cell (RBC) activity was measured by using a radiochemical method and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C in 108 thiopurinetreated pediatric IBD patients with a mean age of 11.3 years (range 3-16). RESULTS Significant TPMT activity differences between wild-type and heterozygous and homozygous mutated subjects were observed. We divided TPMT activity into three categories according to frequency distribution: low (16.67%), intermediate (25.92%) and high (57.41%). The whole population included a total of 77.78% of homozygous wild-type subjects, 15.74% heterozygous variants, 1.85% homozygous variants and five (4.63%) compound heterozygous variant TPMT*3B/*3C. The overall concordance rate between TPMT genotypes and phenotypes was 88.2%. Seven carriers of at least one variant allele and low or intermediate TPMT activity developed adverse effects. CONCLUSIONS Our findings suggest that carriers of at least one variant allele and both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelotoxicity compared with individuals with normal genotype and TPMT activity.
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Chouchana L, Narjoz C, Beaune P, Loriot MA, Roblin X. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2012; 35:15-36. [PMID: 22050052 DOI: 10.1111/j.1365-2036.2011.04905.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter-individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. AIM To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic-based therapeutic recommendations. METHODS We conducted a query on PubMed database using 'inflammatory bowel disease', 'thiopurine', 'azathioprine', '6-mercaptopurine', 'TPMT', 'pharmacogenetics', 'TDM', and selected relevant articles, especially clinical studies. RESULTS Thiopurine metabolism - key enzyme: thiopurine S-methyltransferase (TPMT) - modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6-TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S-transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. CONCLUSIONS Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.
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Affiliation(s)
- L Chouchana
- Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Biochimie, Pharmacogénétique et Oncologie Moléculaire, Paris, France
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Ding L, Zhang FB, Liu H, Gao X, Bi HC, Wang XD, Chen BL, Zhang Y, Zhao LZ, Zhong GP, Hu PJ, Chen MH, Huang M. Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:63-73. [PMID: 21381155 DOI: 10.1002/ibd.21676] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Accepted: 01/13/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Thiopurine drugs are widely used in the treatment of inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and adverse events occurrence. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the effects of TPMT and hypoxanthine guanine phosphoribosyltransferase (HPRT) activities on 6-thioguanine nucleotides (6-TGNs) concentrations and thiopurine-induced leukopenia in patients with IBD. METHODS Clinical data and blood samples were collected from 120 IBD patients who were receiving azathioprine (AZA)/6-mercaptopurine (6-MP) therapy. Erythrocyte TPMT, HPRT activities and 6-TGNs concentrations were determined. HPRT activity and its correlation with TPMT activity, 6-TGNs level, and leukopenia were evaluated. RESULTS The HPRT activity of all patients ranged from 1.63-3.33 (2.31 ± 0.36) μmol/min per g Hb. HPRT activity was significantly higher in patients with leukopenia (27, 22.5%) than without (P < 0.001). A positive correlation between HPRT activity and 6-TGNs concentration was found in patients with leukopenia (r = 0.526, P = 0.005). Patients with HPRT activity > 2.70 μmol/min per g Hb could have an increased risk of developing leukopenia (odds ratio = 7.47, P < 0.001). No correlation was observed between TPMT activity and HPRT activity, 6-TGNs concentration, or leukopenia. CONCLUSIONS High levels of HPRT activity could be a predictor of leukopenia and unsafe 6-TGN concentrations in patients undergoing AZA/6-MP therapy. This could partly explain the therapeutic response or toxicity that could not be adequately explained by the polymorphisms of TPMT.
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Affiliation(s)
- Liang Ding
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China
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Lakatos PL, Kiss LS. Current status of thiopurine analogues in the treatment in Crohn's disease. World J Gastroenterol 2011; 17:4372-4381. [PMID: 22110262 PMCID: PMC3218150 DOI: 10.3748/wjg.v17.i39.4372] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/21/2011] [Accepted: 06/28/2011] [Indexed: 02/06/2023] Open
Abstract
In the last decades, with the development of biological therapy, the treatment paradigms in patients with Crohn's disease have continuously evolved. Several studies focusing on the optimal use of both traditional immunosuppressants and biological therapy have been published, investigating conventional, accelerated step-up and top-down approaches. In addition, much emphasis has been placed in recent years on the determination of important predictive factors that could enable early patient stratification, which would lead to a tailored management strategy. In this review, the authors try to highlight new evidence on the optimal timing, benefits, and risks of immunosuppressants alone, or in combination, in patients with Crohn's disease.
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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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Bahari A, Hashemi M, Bari Z, Moazeni-Roodi A, Kaykhaei MA, Narouie B. Frequency of thiopurine S-methyltransferase (TPMT) alleles in southeast Iranian population. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2010; 29:237-44. [PMID: 20408054 DOI: 10.1080/15257771003720418] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Thiopurine S-methyltransferase (TPMT, EC 2.1.1.67) plays a key role in the metabolism of thioprine drugs. Subjects with intermediate or no TPMT activity are at risk of azathioprines toxicity treated with conventional dosages of thiopurine drugs. While TPMT polymorphisms have been extensively studied in many countries, there is insufficient data in Iranian populations. In the present study, we aimed to identify the common functional TPMT alleles in southeast Iranian population. The TPMT allele frequencies were determined by multiplexed allele-specific polymerase chain reaction. Among 832 samples of Iranian population, the frequency for the TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C, were 2.16%, 1.68%, 1.62%, and 0.54%, respectively. The distribution of the TPMT genotypes were 87.98% for TPMT*1/*1, 4.33% for TPMT*1/*2, 3.36% for TPMT*1/*3A, 3.24% for TPMT*1/*3B, and 1.08% for TPMT*1/*3C. This functional analysis of common TPMT alleles in an Iranian population could provide useful information for thioprine drugs therapy.
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Affiliation(s)
- Ali Bahari
- Department of Internal Medicine, School of Medicine, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
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Abstract
During the course of the disease, most patients with Crohn's disease (CD) may eventually develop a stricturing or a perforating complication, and a significant number of patients with both CD and ulcerative colitis will undergo surgery. In recent years, research has focused on the determination of factors important in the prediction of disease course in inflammatory bowel diseases to improve stratification of patients, identify individual patient profiles, including clinical, laboratory and molecular markers, which hopefully will allow physicians to choose the most appropriate management in terms of therapy and intensity of follow-up. This review summarizes the available evidence on clinical, endoscopic variables and biomarkers in the prediction of short and long-term outcome in patients with inflammatory bowel diseases.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, H-1083 Budapest, Koranyi S 2A, Hungary.
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Thiopurine S-methyltransferase gene polymorphism and 6-mercaptopurine dose intensity in Indian children with acute lymphoblastic leukemia. Leuk Res 2010; 34:1023-6. [DOI: 10.1016/j.leukres.2010.01.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Revised: 01/21/2010] [Accepted: 01/26/2010] [Indexed: 11/23/2022]
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Lakatos PL, Kiss LS. Is the disease course predictable in inflammatory bowel diseases? World J Gastroenterol 2010; 16:2591-2599. [PMID: 20518079 PMCID: PMC2880770 DOI: 10.3748/wjg.v16.i21.2591] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2009] [Revised: 12/16/2009] [Accepted: 12/23/2009] [Indexed: 02/06/2023] Open
Abstract
During the course of the disease, most patients with Crohn's disease (CD) may eventually develop a stricturing or a perforating complication, and a significant number of patients with both CD and ulcerative colitis will undergo surgery. In recent years, research has focused on the determination of factors important in the prediction of disease course in inflammatory bowel diseases to improve stratification of patients, identify individual patient profiles, including clinical, laboratory and molecular markers, which hopefully will allow physicians to choose the most appropriate management in terms of therapy and intensity of follow-up. This review summarizes the available evidence on clinical, endoscopic variables and biomarkers in the prediction of short and long-term outcome in patients with inflammatory bowel diseases.
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Abstract
Clinical presentation at diagnosis and disease course of both Crohn's disease (CD) and ulcerative colitis (UC) are heterogeneous and variable over time. During follow up, intestinal strictures or perforation may eventually develop at most patients with CD, and significant number of patients will undergo surgery. Much emphasis was laid in recent years on the determination of important predictive factors. Since early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. This review article summarizes the available literature on important clinical, endoscopic, fecal, serological/routine laboratory and genetic factors and hopefully will assist clinicians in the decision making of daily practice when choosing the treatment strategy for their patients with inflammatory bowel diseases.
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Affiliation(s)
- Lajos Sándor Kiss
- Semmelweis Egyetem, Altalános Orvostudományi Kar I. Belgyógyászati Klinika Budapest.
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Samochatova EV, Chupova NV, Rudneva A, Makarova O, Nasedkina TV, Fedorova OE, Glotov AS, Kozhekbaeva Z, Maiorova OA, Roumyantsev AG, Krynetski EY, Krynetskaia NF, Evans WE, Ribeiro RC. TPMT genetic variations in populations of the Russian Federation. Pediatr Blood Cancer 2009; 52:203-8. [PMID: 19034904 PMCID: PMC2794198 DOI: 10.1002/pbc.21837] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Polymorphisms that reduce the activity of thiopurine S-methyltransferase (TPMT) cause adverse reactions to conventional doses of thiopurines, routinely used for antileukemic and immunosuppressive treatment. There are more than 20 variant alleles of TPMT that cause decreased enzymatic activity. We studied the most common variant alleles of TPMT and their frequency distribution in a large cohort of multiracial residents in the Russian Federation and compared their frequencies in children with and without malignancy to determine whether TPMT gene abnormality is associated with hematologic malignancy. PROCEDURE The TPMT biochip was used to detect 6 TPMT single nucleotide polymorphisms (SNPs) corresponding to 7 TPMT-deficiency alleles (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C, TPMT*3D, TPMT*7, and TPMT*8). We analyzed allele frequencies in the whole cohort, the childhood cancer group, and the non-cancer group. We also characterized disease features and outcome according to the presence of TPMT SNPs in children with acute lymphoblastic leukemia (ALL). RESULTS Fifty-five (5.5%) study participants overall had heterozygous TPMT genotypes (1 variant and 1 wild-type allele): TPMT*1/*3A (n = 45; 4.5%), TPMT*1/*3C (n = 8; 0.8%), and TPMT*1/*2 (n = 2; 0.2%). TPMT SNPs were more frequent in children with hematologic malignancy than in other participants (7.5% vs. 4.0%, P = 0.02). We found no significant association between TPMT SNPs and ALL treatment outcome (median follow-up, 31.3 months). CONCLUSIONS TPMT*3A is the most prevalent variant allele in the Russian Federation. The estimated frequency of variant alleles in the study cohort (5.5%) was similar to that observed in the White populations in the U.S. and Eastern Europe.
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Affiliation(s)
- Elena V Samochatova
- Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russia, Russian Children’s Clinical Hospital, Moscow, Russia,Correspondence to: Elena V. Samochatova, MD, Federal Research Clinical Center for Pediatric Hematology, Oncology, and Immunology, Leninsky Prospect 117, Moscow 117997, Russia. Fax +7 495 935 55 10; Tel. +7 495 936 90 78;
| | | | - Anastassia Rudneva
- Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russia, Russian Children’s Clinical Hospital, Moscow, Russia
| | - Olga Makarova
- Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russia, Russian Children’s Clinical Hospital, Moscow, Russia
| | - Tatyana V Nasedkina
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Olga E Fedorova
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Andrei S Glotov
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Zh. Kozhekbaeva
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Olga A Maiorova
- Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russia
| | | | - Eugene Y Krynetski
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Natalia F Krynetskaia
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - William E Evans
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Raul C Ribeiro
- Department of Oncology and International Outreach Program, Memphis, Tennessee, USA
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Leung M, Piatkov I, Rochester C, Boyages SC, Leong RWL. Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression. Intern Med J 2009; 39:121-6. [DOI: 10.1111/j.1445-5994.2008.01855.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Szamosi T, Lakatos PL, Szilvasi A, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Szabo O, Satori A, Tulassay Z, Miheller P, Horvath HC, Papp J, Tordai A, Andrikovics H. The 3'UTR NFKBIA variant is associated with extensive colitis in Hungarian IBD patients. Dig Dis Sci 2009; 54:351-359. [PMID: 18716880 DOI: 10.1007/s10620-008-0351-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Accepted: 05/15/2008] [Indexed: 12/09/2022]
Abstract
PURPOSE In previous studies the NFKBIA 3'UTR (untranslated region) AA genotype was associated with Crohn's disease (CD), while the NFKB1-94ins/delATTG mutation increased the risk for ulcerative colitis (UC). The aim of our study was to investigate these two polymorphisms and patients' response to medical therapy and/or disease phenotype in Hungarian inflammatory bowel disease (IBD) patients. METHODS NFKBIA 3'UTR- and NFKB1-94ins/delATTG polymorphisms were investigated in 415 unrelated IBD patients (CD: 266 patients, mean age 35.2 +/- 12.1 years, duration 8.7 +/- 7.5 years; UC patients: 149, mean age 44.4 +/- 15.4 years, duration 10.7 +/- 8.9 years) and 149 controls by PCR-restriction fragment length polymorphism (RFLP) analysis. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS The NFKBIA 3'UTR and NFKB1-94ins/delATTG genotypes and allele frequencies were not significantly different among IBD and controls. In patients with UC, the 3'UTR GG genotype was associated with extensive colitis (55.3 vs. 29.4%, odds ratio 2.97, 95% confidence interval 1.45-6.08). The presence of variant alleles did not predict response to steroids, infliximab, or need for surgery. CONCLUSIONS The NFKBIA 3'UTR GG genotype was associated with an increased risk for extensive colitis in Hungarian patients. In contrast, variant alleles did not predict response to medical therapy or need for surgery.
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Affiliation(s)
- Tamas Szamosi
- 1st Department of Medicine, Semmelweis University, Koranyi st. 2/A, 1083, Budapest, Hungary
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Xin HW, Xiong H, Wu XC, Li Q, Xiong L, Yu AR. Relationships between thiopurine S-methyltransferase polymorphism and azathioprine-related adverse drug reactions in Chinese renal transplant recipients. Eur J Clin Pharmacol 2008; 65:249-55. [DOI: 10.1007/s00228-008-0589-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Accepted: 11/11/2008] [Indexed: 11/27/2022]
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Duplex pyrosequencing of the TPMT⁎3C and TPMT⁎6 alleles in Korean and Vietnamese populations. Clin Chim Acta 2008; 398:82-5. [DOI: 10.1016/j.cca.2008.08.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2008] [Revised: 08/15/2008] [Accepted: 08/18/2008] [Indexed: 11/22/2022]
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Komiyama T, Yajima T, Kubota R, Iwao Y, Sakuraba A, Funakoshi S, Negishi K, Minami I, Tanaka Y, Mae H, Hibi T. Lower doses of 6-mercaptopurine/azathioprine bring enough clinical efficacy and therapeutic concentration of erythrocyte 6-mercaptopurine metabolite in Japanese IBD patients. J Crohns Colitis 2008; 2:315-21. [PMID: 21172230 DOI: 10.1016/j.crohns.2008.05.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2008] [Accepted: 05/06/2008] [Indexed: 01/17/2023]
Affiliation(s)
- Takako Komiyama
- Division of Clinical Pharmacy, Center for Clinical Pharmacy and Clinical Sciences, School of Pharmacy, Kitasato University ; 9-1 Shirokane 5-chome, Minato-ku, Tokyo 108-8641, Japan
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Abstract
Pharmacogenetics covers the genetic variation affecting pharmacokinetics and pharmacodynamics, and their influence on drug-response phenotypes. The genetic variation includes an estimated 15 million single nucleotide polymorphisms (SNPs) and is a key determinator for the interindividual differences in treatment resistance and toxic side effects. As most childhood acute lymphoblastic leukemia treatment protocols include up to 13 different chemotherapeutic agents, the impact of individual SNPs has been difficult to evaluate. So far focus has mainly been on the widely used glucocorticosteroids, methotrexate, and thiopurines, or on metabolic pathways and transport mechanisms that are common to several drugs, such as the glutathione S-transferases. However, beyond the thiopurine methyltransferase polymorphisms, the candidate-gene approach has not established clear associations between polymorphisms and treatment response. In the future, high-throughput, low-cost, genetic platforms will allow screening of hundreds or thousands of targeted SNPs to give a combined gene-dosage effect (=individual SNP risk profile), which may allow pharmacogenetic-based individualization of treatment.
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Chowbay B, Zhou S, Lee EJD. An Interethnic Comparison of Polymorphisms of the Genes Encoding Drug-Metabolizing Enzymes and Drug Transporters: Experience in Singapore. Drug Metab Rev 2008; 37:327-78. [PMID: 15931768 DOI: 10.1081/dmr-28805] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Much of the interindividual variability in drug response is attributable to the presence of single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes and drug transporters. In recent years, we have investigated the polymorphisms in a number of genes encoding phase I and II drug-metabolizing enzymes including CYPIA1, CYP3A4, CYP3A5, GSTM1, NAT2, UGT1A1, and TPMT and drug transporter (MDR1) in three distinct Asian populations in Singapore, namely the Chinese, Malays, and Indians. Significant differences in the frequencies of common alleles encoding these proteins have been observed among these three ethnic groups. For example, the frequency of the variant A2455G polymorphism of CYP1A1 was 28% in Chinese and 31% in Malays, but only 18% in Indians. CYP3A4*4 was detected in two of 110 Chinese subjects, but absent in Indians and Malays. Many Chinese and Malays (61-63%) were homozygous for the GSTM1*0 null genotype compared with 33% of Indians. The frequency of the UGTIA1*28 allele was highest in the Indian population (35%) compared to similar frequencies that were found in the Chinese (16%) and Malay (19%) populations. More importantly, our experience over the years has shown that the pharmacogenetics of these drug-metabolizing enzymes and MDR1 in the Asian populations are different from these in the Caucasian and African populations. For example, the CYP3A4*1B allele, which contains an A-290G substitution in the promoter region of CYP3A4, is absent in all three Asian populations of Singapore studied, but occurs in more than 54% of Africans and 5% of Caucasians. There were no difference in genotype and allelic variant frequencies in exon 12 of MDR1 between the Chinese, Malay, and Indian populations. When compared with other ethnic groups, the distribution of the wild-type C allele in exon 12 in the Malays (34.2%) and Indians (32.8%) was relatively high and similar to the Japanese (38.55%) and Caucasians (41%) but different from African-Americans (15%). The frequency of wild-type TT genotype in Asians (43.5% to 52.1%) and Japanese (61.5%) was much higher than those found in Caucasians (13.3%). All the proteins we studied represent the primary hepatic or extrahepatic enzymes, and their polymorphic expression may be implicated in disease risk and the disposition of drugs or endogenous substances. As such, dose requirements of certain drugs may not be optimal for Asian populations, and a second look at the factors responsible for this difference is necessary.
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Affiliation(s)
- Balram Chowbay
- Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore
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Rutherford K, Daggett V. Four human thiopurine s-methyltransferase alleles severely affect protein structure and dynamics. J Mol Biol 2008; 379:803-14. [PMID: 18482735 PMCID: PMC2518407 DOI: 10.1016/j.jmb.2008.04.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Revised: 03/29/2008] [Accepted: 04/11/2008] [Indexed: 10/22/2022]
Abstract
Thiopurine S-methyltransferase (TPMT) metabolizes cytotoxic thiopurine drugs used in the treatment of leukemia and inflammatory bowel disease. TPMT is a major pharmacogenomic target with 23 alleles identified to date. Several of these alleles cause rapid protein degradation and/or aggregation, making it extremely difficult to study the structural impact of the TPMT polymorphisms experimentally. We, therefore, have performed multiple molecular dynamics simulations of the four most common alleles [TPMT*2 (A80P), *3A (A154T/Y240C), *3B (A154T) and *3C (Y240C)] to investigate the molecular mechanism of TPMT inactivation at an atomic level. The A80P polymorphism in TPMT*2 disrupts helix alpha3 bordering the active site, which breaks several salt-bridge interactions and opens up a large cleft in the protein. The A154T polymorphism is located within the co-substrate binding site. The larger threonine alters the packing of substrate-binding residues (P68, L69, Y166), increasing the solvent exposure of the polymorphic site. This packing rearrangement may account for the complete lack of activity in the A154T mutant. The Y240C polymorphism is located in beta-strand 9, distant from the active site. Side-chain contacts between residue 240 and helix alpha8 are lost in TPMT*3C. Residues 154 and 240 in TPMT*3A are connected through a hydrogen-bonding network. The dual polymorphisms result in a flattened, slightly distorted protein structure and an increase in the thiopurine-binding site solvent accessibility. The two variants that undergo the most rapid degradation in vivo, TPMT*2 and *3A, are also the most deformed in the simulations.
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Affiliation(s)
- Karen Rutherford
- Department of Biochemistry, University of Washington, Seattle WA 98195-5013
| | - Valerie Daggett
- Department of Biochemistry, University of Washington, Seattle WA 98195-5013
- Department of Bioengineering, University of Washington, Seattle WA 98195-5013
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Garat A, Cauffiez C, Renault N, Lo-Guidice JM, Allorge D, Chevalier D, Houdret N, Chavatte P, Loriot MA, Gala JL, Broly F. Characterisation of novel defective thiopurine S-methyltransferase allelic variants. Biochem Pharmacol 2008; 76:404-15. [PMID: 18602085 DOI: 10.1016/j.bcp.2008.05.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Revised: 04/29/2008] [Accepted: 05/01/2008] [Indexed: 10/22/2022]
Abstract
Human thiopurine S-methyltransferase (TPMT, EC 2.1.1.67) is a key enzyme in the detoxification of thiopurine drugs widely used in the treatment of various diseases, such as inflammatory bowel diseases, acute lymphoblastic leukaemia and rheumatic diseases. The TPMT gene is genetically polymorphic and the inverse relationship between TPMT activity and the risk of developing severe hematopoietic toxicity is well known. In this study, the entire coding sequence of TPMT, together with its 5'-flanking promoter region, was analysed in patients with an intermediate phenotype for thiopurine drug methylation. Four polymorphisms were identified, two previously described, c.356A>C (p.Lys(119)Thr, TPMT*9) and c.205C>G (p.Leu(69)Val, TPMT*21), and two novel missense mutations, c.537G>T (p.Gln(179)His, TPMT*24) and c.634T>C (p.Cys(212)Arg, TPMT*25). Structural investigations, using molecular modeling, were undertaken in an attempt to explain the potential impact of the amino acid substitutions on the structure and activity of the variant proteins. Additionally, in order to determine kinetic parameters (K(m) and V(max)) of 6-thioguanine (6-TG) methylation, the four variants were expressed in a recombinant yeast expression system. Assays were performed by HPLC and the results were compared with those of wild-type TPMT. The p.Leu(69)Val and the p.Cys(212)Arg substitutions encode recombinant enzymes with a significantly decreased intrinsic clearance compared to that of the wild-type protein, and, consequently, characterise non-functional alleles of TPMT. The p.Lys(119)Thr and the p.Gln(179)His substitutions do not affect significantly the catalytic activity of the corresponding variant proteins, which prevents to unambiguously describe these latter alleles as defective TPMT variants.
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Affiliation(s)
- A Garat
- Equipe d'accueil 2679, Faculté de Médecine de Lille, Pôle Recherche, Lille, France
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