Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.
J Gastroenterol
; 56(11): 999-1007, 2021 11.
Article
in En
| MEDLINE
| ID: mdl-34480209
ABSTRACT
BACKGROUND AND AIMS:
Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes.METHODS:
DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTGPBMC was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4+ T lymphocytes with 6-thioguanine (6-TG).RESULTS:
dTGPBMC was significantly higher in NUDT15 variants than in non-variants. dTGPBMC, but not 6-TGNRBC, negatively correlated with peripheral lymphocyte counts (r = - 0.31 and - 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis.CONCLUSION:
Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrophosphatases
/
Inflammatory Bowel Diseases
/
Leukopenia
/
Methyltransferases
Type of study:
Observational_studies
/
Prevalence_studies
/
Risk_factors_studies
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Country/Region as subject:
Asia
Language:
En
Journal:
J Gastroenterol
Journal subject:
GASTROENTEROLOGIA
Year:
2021
Document type:
Article
Affiliation country:
Japan
Publication country:
JAPAN
/
JAPON
/
JAPÃO
/
JP