Rechercher
image du produit
Biomedicine and pharmacotherapy

S'abonner

DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease - 08/12/22

Doi : 10.1016/j.biopha.2022.113901 
Davide Selvestrel a, Gabriele Stocco b, c, Marina Aloi d, Serena Arrigo e, Sabrina Cardile f, Erika Cecchin g, Mauro Congia h, Debora Curci b, Simona Gatti i, Francesco Graziano j, Carl D. Langefeld k, Marianna Lucafò c, Stefano Martelossi l, Massimo Martinelli m, Sofia Pagarin c, Luca Scarallo n, Elisabetta Francesca Stacul o, Caterina Strisciuglio p, Susan Thompson q, Giovanna Zuin r, Giuliana Decorti b, c, ⁎ , Matteo Bramuzzo s
a Department of Life Sciences, University of Trieste, Trieste, Italy 
b Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy 
c Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy 
d Women’s and Children’s Health Department, Pediatric Gastroenterology and Hepatology Unit, Sapienza University of Rome, Rome, Italy 
e Pediatric Gastroenterology and Endoscopy Unit, Institute ’Giannina Gaslini’, Genoa, Italy 
f Hepatology and Gastroenterology Unit, Bambino Gesù Hospital, Rome, Italy 
g Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy 
h Pediatric Clinic and Rare Diseases, Microcitemic Pediatric Hospital Antonio Cao, Azienda Ospedaliera Brotzu, Cagliari, Italy 
i Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy 
j Pediatric Unit, Villa Sofia Cervello Hospital, Palermo, Italy 
k Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA 
l Pediatric Unit, Ca’ Foncello’s Hospital, Treviso, Italy 
m Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy 
n University of Florence-Meyer Hospital, Florence, Italy 
o Department of Pediatrics, Niguarda Hospital, Milan, Italy 
p Departement of Woman, Child and General and Specialistic Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy 
q Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA 
r Department of Pediatrics, University of Milano-Bicocca, Foundation MBBM/San Gerardo Hospital, Monza, Italy 
s Gastroenterology, Digestive Endoscopy and Nutrition Unit, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo”, Trieste, Italy 

⁎Correspondence to: Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.Department of Medicine, Surgery and Health Sciences, University of TriesteTriesteItaly

Abstract

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

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

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

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 ×10−5). No differences in TPMT promoter methylation were found. Reduced cg22736354 methylation was associated with lower TGN concentrations (rho = 0.31, p = 0.01) in patients with VEO-IBD and aIBD.

Conclusion

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.

Le texte complet de cet article est disponible en PDF.

Graphical Abstract




ga1

Le texte complet de cet article est disponible en PDF.

Highlights

•
The activity of TPMT, is higher in VEO-IBD than in adolescents with IBD.
•
DNA methylation of cg22736354 located in the TPMT gene neighborhood is lower in VEO-IBD patients.
•
DNA methylation of cg22736354 is associated with reduced azathioprine active metabolites.
•
cg22736354 methylation might regulate azathioprine pharmacokinetics in young patients with IBD.

Le texte complet de cet article est disponible en PDF.

Abbreviations : ANOVA, CD, CpG, FDR, HPLC, IBD, IQR, MMPN, SNP, TGN, TPMT, UC, VEO-IBD, aIBD

Keywords : Azathioprine, DNA methylation, TPMT, Very early onset inflammatory bowel disease


Plan


© 2022  The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
Ajouter à ma bibliothèque Retirer de ma bibliothèque Imprimer
Export

    Export citations

  • Fichier

    •

  • Contenu

    •

Vol 157

Article 113901- janvier 2023 Retour au numéro
Article précédent Article précédent
  • Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes
  • Andrew N. Hakeem, Mohamed M. Kamal, Rasha A. Tawfiq, Basma A. Abdelrahman, Olfat A. Hammam, Mohamed M. Elmazar, Aiman S. El-Khatib, Yasmeen M. Attia
| Article suivant Article suivant
  • Cyanidin 3-glucoside targets a hepatic bilirubin transporter in rats
  • Paola Pelizzo, Marco Stebel, Nevenka Medic, Paola Sist, Andreja Vanzo, Andrea Anesi, Urska Vrhovsek, Federica Tramer, Sabina Passamonti

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL

EM-CONSULTE.COM est déclaré à la CNIL, déclaration n° 1286925.

En application de la loi nº78-17 du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés, vous disposez des droits d'opposition (art.26 de la loi), d'accès (art.34 à 38 de la loi), et de rectification (art.36 de la loi) des données vous concernant. Ainsi, vous pouvez exiger que soient rectifiées, complétées, clarifiées, mises à jour ou effacées les informations vous concernant qui sont inexactes, incomplètes, équivoques, périmées ou dont la collecte ou l'utilisation ou la conservation est interdite.
Les informations personnelles concernant les visiteurs de notre site, y compris leur identité, sont confidentielles.
Le responsable du site s'engage sur l'honneur à respecter les conditions légales de confidentialité applicables en France et à ne pas divulguer ces informations à des tiers.

Tout le contenu de ce site: Copyright © 2025 Elsevier, ses concédants de licence et ses contributeurs. Tout les droits sont réservés, y compris ceux relatifs à l'exploration de textes et de données, a la formation en IA et aux technologies similaires. Pour tout contenu en libre accès, les conditions de licence Creative Commons s'appliquent.