The impact of single nucleotide polymorphisms in ADORA2A and ADORA3 genes on the early response to methotrexate and presence of therapy side effects in children with juvenile idiopathic arthritis: Results of a preliminary study

Int J Rheum Dis. 2020 Nov;23(11):1505-1513. doi: 10.1111/1756-185X.13972. Epub 2020 Sep 23.


Aim: Methotrexate (MTX) administered at the dose 10-15 mg/m2 is recommended as the first-line therapy in most juvenile idiopathic arthritis (JIA) subtypes. The disease-modifying effect of methotrexate is associated with release of adenosine and mediated via binding to adenosine receptor A2A (ADORA2A) and 3 (ADORA3). The aim of our study was to determine the association between single nucleotide polymorphisms in ADORA2A (rs2236624, rs2298383) and ADORA3 (rs3393) receptor genes on the disease activity and presence of MTX therapy side effects in patients with JIA.

Methods: One hundred children with JIA of all subtypes treated with MTX were recruited to the study. Demographic and clinical parameters were collected at the baseline of MTX therapy and on a control visit 4-6 months after starting MTX. Single nucleotide polymorphism genotyping was performed using genomic DNA isolated from peripheral blood samples.

Results: The polymorphic variant of ADORA2A rs2236624 was associated with ~3.5 times higher odds of gastrointestinal side effects occurrence (odds ratio: 3.59, 95% CI: 1.15-11.22, P = 0.0282). Children with the ADORA3 rs3393 polymorphic variants (CT/CC) after 6 months of MTX treatment had significantly lower number of joints with active arthritis (median: 0.00 vs 1.00, P = 0.0400) and value of C-reactive protein (0.60 vs 2.40, P = 0.0242) in comparison to TT variant.

Conclusion: Although future studies are needed to verify our findings, polymorphisms in ADORA2A and ADORA3 genes may become the determinants of MTX treatment efficacy and gastrointestinal toxicity in children with JIA.

Keywords: juvenile idiopathic arthritis; methotrexate; single nucleotide polymorphism.

Publication types

  • Comparative Study

MeSH terms

  • Age Factors
  • Arthritis, Juvenile / diagnosis
  • Arthritis, Juvenile / drug therapy*
  • Arthritis, Juvenile / genetics
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Male
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use*
  • Pharmacogenetics
  • Pharmacogenomic Variants*
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Receptor, Adenosine A2A / genetics*
  • Receptor, Adenosine A3 / genetics*
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome


  • ADORA2A protein, human
  • ADORA3 protein, human
  • Immunosuppressive Agents
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3
  • Methotrexate