MANCHESTER, United Kingdom—Five variants of the adenosine receptor 2a gene (ADORA2a) are associated with adverse events (AEs), particularly gastrointestinal (GI) toxicity in rheumatoid arthritis (RA) patients treated with methotrexate (MTX). Sam L. Hider, MD, and colleagues report early online in Rheumatology that although there was no association between these single nucleotide polymorphisms (SNPs) and methotrexate efficacy, they might provide a useful screen for identifying patients at high risk of methotrexate-related GI toxicity.1

"These results support the work of others suggesting that the outcome of MTX therapy is, in part, genetically determined."—Sam L. Hider, MD
“[W]e report a novel association between ADORA2a polymorphisms and AEs in MTX-treated RA patients. Specifically, associations were observed between several ADORA2a SNPs and GI AEs on MTX. These results support the work of others suggesting that the outcome of MTX therapy is, in part, genetically determined,” Dr. Hider said.

Dr. Hider, who is from the ARC Epidemiology Unit at the University of Manchester, UK, conducted a retrospective study of RA patients from the University Hospital of North Staffordshire and from the Central Manchester and Manchester Children's University Hospitals Trust. The study included patients who had good responses to MTX (n = 147), patients for whom MTX was ineffective (n = 101), and patients with treatment failure due to AEs (n = 61). The AEs were subdivided into GI toxicity, abnormal liver function tests (LFTs), and other toxicities.

Eight SNPs within the ADORA2a gene were analyzed. Five of these were significantly associated with AEs:
  • rs 5760410
  • rs 2298383
  • rs 3761422
  • rs 2267076
  • rs 2236624

The odds of having any AE due to treatment with MTX were significantly higher for RA patients with any one of these variants. The odds specific to GI toxicity were significantly higher with rs 5760410 and with rs 2236624.

“Overall, these SNPs were significantly associated with any AEs at all 5 loci (OR 2.1-3.07, P <.05 for all). In subgroup analysis, carriage of the variant allele was significantly associated with GI AEs at 2 of the 5 loci. Although the numbers are small, homozygosity of the variant allele was associated with GI AEs at four loci (OR 2.9-5.9, P<.05),” the authors wrote.

Reference

1. Hider SL, Thomson W, Mack LF, et al. Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX. Rheumatology.  2008;47:1156-1159.