PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients

Autor: Nagua Giurici, Diego Favretto, Antonella Colombini, Raffaella Franca, Irene Del Rizzo, Andrea Biondi, Franco Locatelli, Alessandro Ventura, Giuliana Decorti, Gabriele Stocco, S. Martellossi, Marco Pelin, Franca Fagioli, Elena Barisone, Marco Rabusin, Luciana Vinti
Přispěvatelé: Franca, R, Stocco, G, Favretto, D, Giurici, N, del Rizzo, I, Locatelli, F, Vinti, L, Biondi, A, Colombini, A, Fagioli, F, Barisone, E, Pelin, M, Martellossi, S, Ventura, A, Decorti, G, Rabusin, M, Franca, R., Stocco, G., Favretto, D., Giurici, N., del Rizzo, I., Locatelli, F., Vinti, L., Biondi, A., Colombini, A., Fagioli, F., Barisone, E., Pelin, M., Martellossi, S., Ventura, A., Decorti, G., Rabusin, M.
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
genotype
Pediatric patients
population
Thiopurine pharmacokinetic
030226 pharmacology & pharmacy
Gastroenterology
Inflammatory bowel disease
polymorphism
Cohort Studies
0302 clinical medicine
Polymorphism (computer science)
Azathioprine
Genotype
Child
pharmacogenetics
Thiopurine methyltransferase
biology
tpmt
Mercaptopurine
implementation consortium guidelines
s-methyltransferase
therapy
azathioprine
determinant
Middle Aged
Precursor Cell Lymphoblastic Leukemia-Lymphoma
TPMT
thiopurine
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
Italy
Child
Preschool
Cohort
Molecular Medicine
Female
PACSIN2 rs2413739
pediatric patients
acute lymphoblastic leukemia
inflammatory bowel disease
pediatric patient
medicine.drug
thiopurine pharmacokinetics
Adult
medicine.medical_specialty
Adolescent
Polymorphism
Single Nucleotide
03 medical and health sciences
Pharmacokinetics
thiopurine
Internal medicine
Genetics
medicine
Humans
Adverse effect
Adaptor Proteins
Signal Transducing
Pharmacology
business.industry
Inflammatory Bowel Diseases
medicine.disease
030104 developmental biology
biology.protein
business
Zdroj: The Pharmacogenomics Journal. 20:415-425
ISSN: 1473-1150
1470-269X
Popis: 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, howeverazathioprine 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.
Databáze: OpenAIRE
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