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Clinical pharmacogenetic models of treatment response to methotrexate monotherapy in Slovenian and Serbian rheumatoid arthritis patients : differences in patient's management may preclude generalization of the models
Jenko Bizjan, Barbara (Author), Tomšič, Matija (Author), Jekić, Biljana (Author), Milić, Vera (Author), Dolžan, Vita (Author), Praprotnik, Sonja (Author)

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Abstract
Objectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients. Methods: In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients. Results: A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (SLC19A1) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) rs2306283, Thymidylate Synthase (TYMS), and Adenosine Monophosphate Deaminase 1 (AMPD1) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients. Conclusions: We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups.

Language:English
Keywords:rheumatoid arthritis, pharmacogenetics, methotrexate, polymorphism, predictive model
Work type:Article (dk_c)
Tipology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
Year:2018
Number of pages:8 str.
Numbering:Vol. 9, art. 20
UDC:615
ISSN on article:1663-9812
DOI:10.3389/fphar.2018.00020 This link opens in a new window
COBISS.SI-ID:33649113 This link opens in a new window
Views:110
Downloads:37
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Record is a part of a journal

Title:Frontiers in pharmacology
Shortened title:Front Pharmacol
Publisher:Frontiers Media
ISSN:1663-9812
COBISS.SI-ID:29551833 This link opens in a new window

Document is financed by a project

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:P1-0170
Name:Molekulski mehanizmi uravnavanja celičnih procesov v povezavi z nekaterimi boleznimi pri človeku

Funder:MESTD - Ministry of Education, Science and Technological Development of Republic of Serbia
Funding Programme:Basic Research (BR or ON)
Project no.:175091
Name:The Analysis of Genetic Markers of Muscle Dystonia

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:25.01.2018

Secondary language

Language:Slovenian
Keywords:revmatoidni artritis, metotreksat, farmakogenetika, polimorfizem, napovedni model

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