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ADORA2A Polymorphisms Influence Methotrexate Adverse Events in Rheumatoid Arthritis

Nadja Kobold1, Barbara Jenko1, Matija Tomšič2,3

  • 1Institute of Biochemistry, Pharmacogenetics Laboratory, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

The Israel Medical Association Journal : IMAJ
|May 30, 2019
PubMed
Abstract

Insights

Single nucleotide polymorphisms in ADORA2A and ADORA3 genes may influence rheumatoid arthritis treatment with methotrexate. Certain ADORA2A gene variants are linked to fewer adverse events, suggesting potential as biomarkers for methotrexate therapy.

Area of Science:

  • Pharmacogenomics
  • Rheumatology
  • Molecular Biology

Background:

  • Methotrexate is a primary treatment for rheumatoid arthritis (RA), working by increasing adenosine levels.
  • Adenosine's anti-inflammatory effects are mediated through adenosine receptors 2A (ADORA2A) and 3 (ADORA3).
  • Genetic variations, specifically single nucleotide polymorphisms (SNPs) in ADORA2A and ADORA3, are common and may impact drug response.

Purpose of the Study:

  • To determine if specific tagging polymorphisms in the ADORA2A and ADORA3 genes affect patient response to methotrexate treatment for RA.
  • To identify potential genetic biomarkers for predicting methotrexate efficacy and adverse events in RA patients.

Main Methods:

  • Genotyping of 212 RA patients treated with methotrexate for selected tagging SNPs in ADORA2A and ADORA3 genes.
  • Analysis of associations between specific SNPs (e.g., ADORA3 rs35511654, ADORA2A rs2298383, rs2236624, rs5751876, rs35320474) and treatment outcomes.
  • Statistical analysis, including adjustments for clinical factors and haplotype analyses, to confirm significance.

Main Results:

  • A trend towards better methotrexate response was observed in RA patients with the ADORA3 rs35511654 G allele (P = 0.054).
  • Carriers of specific ADORA2A polymorphic alleles (rs2298383, rs2236624, rs5751876, rs35320474) showed a significantly lower likelihood of experiencing methotrexate-induced adverse events (P < 0.05).
  • All identified associations remained statistically significant after adjusting for clinical factors and were supported by haplotype analyses.

Conclusions:

  • Polymorphisms within the ADORA2A gene appear to influence the effectiveness and tolerability of methotrexate treatment in rheumatoid arthritis.
  • These ADORA2A gene variants show promise as predictive biomarkers for optimizing methotrexate therapy in RA patients.
  • Further research into ADORA2A and ADORA3 polymorphisms could lead to personalized treatment strategies for rheumatoid arthritis.

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