Exome-wide pharmacogenomic analysis of response to thiopurines in inflammatory bowel disease patients

Author(s): William Zabala, Raquel Cruz, Manuel Barreiro-de Acosta, María Chaparro, Julián Panes, Ana Echarri, Maria Esteve, Daniel Carpio, Montserrat Andreu, Esther Garcia-Planella, Eugeni Domenech, Angel Carracedo, Javier P. Gisbert, Francisco Barros, on behalf of EIGA and ENEIDA investigators

Journal Name: Current Pharmacogenomics and Personalized Medicine
Formerly Current Pharmacogenomics

Volume 13 , Issue 1 , 2015

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Background: The response to thiopurine treatment in inflammatory bowel disease patients differs greatly among individuals and nearly 50% of patients experience no benefit. Several factors have been implicated in determining this response, including individual genetic variation.

Methods: Aiming to identify genes involved in the response to thiopurine drugs, a two-stage investigation of 20,000 coding single-nucleotide polymorphisms (cSNPs) in 10,000 genes was performed in a Spanish cohort of 257 individuals, 193 showing steroid free remission versus 64 non responder individuals 12 months after initial dose of the drug. The 20 top cSNPs with lower p-values for the association test identified at the first stage (133 responders / 34 non responders), were replicated in a second cohort (60 responders / 30 non responders).

Results: Whereas not statistically significant in all of the two analyzed cohorts, the consistent across samples direction of the observed associations and the allelic joined analysis suggest a significant risk for lack of response related to two genes, PION and ZNF673. With a CMH p-value= 4.26x-06, the associated PION cSNP (rs17151692) minor A allele increases risk for treatment failure 4.5 times when all data is combined.

Conclusion: These findings might help to understand the biological mechanisms behind thiopurine treatment failure and to tailor treatment for individual inflammatory bowel disease patients.

Keywords: Inflammatory bowel disease, pharmacogenetics, response, thiopurine.

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Article Details

Year: 2015
Page: [61 - 67]
Pages: 7
DOI: 10.2174/1875692113666150813151413

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PDF: 28