DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease.

Adolescent Child Humans Azathioprine / therapeutic use DNA Methylation / genetics Methyltransferases / genetics Inflammatory Bowel Diseases / drug therapy Immunosuppressive Agents / therapeutic use
Azathioprine DNA methylation TPMT Very early onset inflammatory bowel disease

Journal

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295

Informations de publication

Date de publication:
Jan 2023
Historique:
received: 20 06 2022
revised: 12 10 2022
accepted: 17 10 2022
pubmed: 4 12 2022
medline: 15 12 2022
entrez: 3 12 2022
Statut: ppublish

Résumé

Thiopurine methyltransferase (TPMT) is a crucial enzyme for azathioprine biotransformation and its activity is higher in very early onset inflammatory bowel disease (VEO-IBD) patients than in adolescents with IBD (aIBD). The aims of this pharmacoepigenetic study were to evaluate differences in peripheral blood DNA methylation of the TPMT gene and in azathioprine pharmacokinetics in patients with VEO-IBD compared to aIBD. The association of age with whole genome DNA methylation profile was evaluated in a pilot group of patients and confirmed by a meta-analysis on 3 cohorts of patients available on the public functional genomics data repository. Effects of candidate CpG sites in the TPMT gene were validated in a larger cohort using pyrosequencing. TPMT activity and azathioprine metabolites (TGN) were measured in patients' erythrocytes by HPLC and associated with patients' age group and TPMT DNA methylation. Whole genome DNA methylation pilot analysis, combined with the meta-analysis revealed cg22736354, located on TPMT downstream neighboring region, as the only statistically significant CpG whose methylation increases with age, resulting lower in VEO-IBD patients compared to aIBD (median 9.6% vs 12%, p = 0.029). Pyrosequencing confirmed lower cg22736354 methylation in VEO-IBD patients (median 4.0% vs 6.0%, p = 4.6 ×10 Methylation of cg22736354 in TPMT gene neighborhood is lower in patients with VEO-IBD and is associated with reduced azathioprine inactivation and increased TGN concentrations.

Sections du résumé

BACKGROUND BACKGROUND
Thiopurine methyltransferase (TPMT) is a crucial enzyme for azathioprine biotransformation and its activity is higher in very early onset inflammatory bowel disease (VEO-IBD) patients than in adolescents with IBD (aIBD).
AIMS OBJECTIVE
The aims of this pharmacoepigenetic study were to evaluate differences in peripheral blood DNA methylation of the TPMT gene and in azathioprine pharmacokinetics in patients with VEO-IBD compared to aIBD.
METHODS METHODS
The association of age with whole genome DNA methylation profile was evaluated in a pilot group of patients and confirmed by a meta-analysis on 3 cohorts of patients available on the public functional genomics data repository. Effects of candidate CpG sites in the TPMT gene were validated in a larger cohort using pyrosequencing. TPMT activity and azathioprine metabolites (TGN) were measured in patients' erythrocytes by HPLC and associated with patients' age group and TPMT DNA methylation.
RESULTS RESULTS
Whole genome DNA methylation pilot analysis, combined with the meta-analysis revealed cg22736354, located on TPMT downstream neighboring region, as the only statistically significant CpG whose methylation increases with age, resulting lower in VEO-IBD patients compared to aIBD (median 9.6% vs 12%, p = 0.029). Pyrosequencing confirmed lower cg22736354 methylation in VEO-IBD patients (median 4.0% vs 6.0%, p = 4.6 ×10
CONCLUSION CONCLUSIONS
Methylation of cg22736354 in TPMT gene neighborhood is lower in patients with VEO-IBD and is associated with reduced azathioprine inactivation and increased TGN concentrations.

Identifiants

DOI: 10.1016/j.biopha.2022.113901 PMID: 36462311
pubmed: 36462311
pii: S0753-3322(22)01290-2
doi: 10.1016/j.biopha.2022.113901
pii:
doi:

Substances chimiques

Azathioprine MRK240IY2L
thiopurine methyltransferase EC 2.1.1.67
Methyltransferases EC 2.1.1.-
Immunosuppressive Agents 0

Types de publication

Meta-Analysis Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

113901

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest statement All authors read and approved the final manuscript. All authors have no conflict of interest.

Auteurs

Davide Selvestrel (D)

Department of Life Sciences, University of Trieste, Trieste, Italy.

Gabriele Stocco (G)

Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Marina Aloi (M)

Women's and Children's Health Department, Pediatric Gastroenterology and Hepatology Unit, Sapienza University of Rome, Rome, Italy.

Serena Arrigo (S)

Pediatric Gastroenterology and Endoscopy Unit, Institute 'Giannina Gaslini', Genoa, Italy.

Sabrina Cardile (S)

Hepatology and Gastroenterology Unit, Bambino Gesù Hospital, Rome, Italy.

Erika Cecchin (E)

Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.

Mauro Congia (M)

Pediatric Clinic and Rare Diseases, Microcitemic Pediatric Hospital Antonio Cao, Azienda Ospedaliera Brotzu, Cagliari, Italy.

Debora Curci (D)

Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.

Simona Gatti (S)

Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy.

Francesco Graziano (F)

Pediatric Unit, Villa Sofia Cervello Hospital, Palermo, Italy.

Carl D Langefeld (CD)

Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Marianna Lucafò (M)

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Stefano Martelossi (S)

Pediatric Unit, Ca' Foncello's Hospital, Treviso, Italy.

Massimo Martinelli (M)

Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples, Italy.

Sofia Pagarin (S)

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Luca Scarallo (L)

University of Florence-Meyer Hospital, Florence, Italy.

Elisabetta Francesca Stacul (EF)

Department of Pediatrics, Niguarda Hospital, Milan, Italy.

Caterina Strisciuglio (C)

Departement of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

Susan Thompson (S)

Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.

Giovanna Zuin (G)

Department of Pediatrics, University of Milano-Bicocca, Foundation MBBM/San Gerardo Hospital, Monza, Italy.

Giuliana Decorti (G)

Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy. Electronic address: decorti@units.it.

Matteo Bramuzzo (M)

Gastroenterology, Digestive Endoscopy and Nutrition Unit, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Thionucléosides › Azathioprine › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies inflammatoires intestinales › DNA methylation of the TPMT gene and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Immunosuppresseurs › DNA methylation of the TPMT gene and...