%0 Meta-Analysis
%T DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease.
%A Selvestrel D
%A Stocco G
%A Aloi M
%A Arrigo S
%A Cardile S
%A Cecchin E
%A Congia M
%A Curci D
%A Gatti S
%A Graziano F
%A Langefeld CD
%A Lucafò M
%A Martelossi S
%A Martinelli M
%A Pagarin S
%A Scarallo L
%A Stacul EF
%A Strisciuglio C
%A Thompson S
%A Zuin G
%A Decorti G
%A Bramuzzo M
%J Biomed Pharmacother
%V 157
%N 0
%D Jan 2023
%M 36462311
%F 7.419
%R 10.1016/j.biopha.2022.113901
%X <B>BACKGROUND: </B>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).<BR><B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.