PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients.
Adaptor Proteins, Signal Transducing
/ genetics
Adolescent
Adult
Azathioprine
/ adverse effects
Child
Child, Preschool
Cohort Studies
Female
Humans
Inflammatory Bowel Diseases
/ drug therapy
Italy
/ epidemiology
Male
Mercaptopurine
/ adverse effects
Middle Aged
Polymorphism, Single Nucleotide
/ drug effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
Journal
The pharmacogenomics journal
ISSN: 1473-1150
Titre abrégé: Pharmacogenomics J
Pays: United States
ID NLM: 101083949
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
08
02
2019
accepted:
20
11
2019
revised:
09
11
2019
pubmed:
4
12
2019
medline:
8
5
2021
entrez:
4
12
2019
Statut:
ppublish
Résumé
The aim of the study was to validate the impact of the single-nucleotide polymorphism rs2413739 (T > C) in the PACSIN2 gene on thiopurines pharmacological parameters and clinical response in an Italian cohort of pediatric patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD). In ALL, PACSIN2 rs2413739 T allele was associated with a significant reduction of TPMT activity in erythrocytes (p = 0.0094, linear mixed-effect model, multivariate analysis considering TPMT genotype) and increased severe gastrointestinal toxicity during consolidation therapy (p = 0.049). A similar trend was present also for severe hematological toxicity during maintenance. In IBD, no significant effect of rs2413739 could be found on TPMT activity, however azathioprine effectiveness was reduced in patients carrying the T allele (linear mixed effect, p = 0.0058). In PBMC from healthy donors, a positive correlation between PACSIN2 and TPMT protein concentration could be detected (linear mixed effect, p = 0.045). These results support the role of PACSIN2 polymorphism on TPMT activity and mercaptopurine adverse effects in patients with ALL. Further evidence on PBMC and pediatric patients with IBD supports an association between PACSIN2 variants, TPMT activity, and thiopurines effects, even if more studies are needed since some of these effects may be tissue specific.
Identifiants
pubmed: 31792371
doi: 10.1038/s41397-019-0130-0
pii: 10.1038/s41397-019-0130-0
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
PACSIN2 protein, human
0
Mercaptopurine
E7WED276I5
Azathioprine
MRK240IY2L
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
415-425Références
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