Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Genetic Polymorphisms in Key Methotrexate (MTX) Pathway Genes Associated with Response to MTX Treatment in Rheumatoid Arthritis.
Owen2, Sally-Anne, Eyre2, Stephen, Martin2, Paul, Hider1, Samantha, Bruce2, Ian N., Barton2, Anne, Thomson2, Wendy
Methotrexate (MTX) is the cornerstone of treatment for rheumatoid arthritis (RA). However, up to a third of individuals will fail to respond to MTX treatment or suffer adverse events (AE). The main determinates of MTX response in RA remain unclear although evidence suggests that part of this variability is genetic. Genes within the MTX metabolic pathway represent good candidates as predictors of response. We investigated SNPs spanning 11 MTX pathway genes on the efficacy and occurrence of AE in MTX treated patients with RA.
Subjects included 309 RA patients with a defined response to MTX. Patients were included if they were (i) good responders (n=147) (with an ESR <20 and/or normal CRP and on a stable dose of MTX for at least 6mths) (ii) inefficacy failures (n=101) (physician statement and failure to reduce ESR/CRP by 20%) or (iii) AE failures (n=61) (verified by medical record review). Tagging SNPs were selected for genes: AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, MTHFR, SHMT1, SLC19A1 (RFC) and TYMS using an r2 cutoff >= 0.8 and MAF >= 0.05 within 10kb up and down stream of each gene. Genotyping was performed using the Sequenom iPlex® MassARRAY platform. Three different analyses were conducted: 1) responders vs inefficacy failures 2) responders vs AE failures and 3) responders vs inefficacy and AE failures combined. Genotype frequencies were compared between the groups using the trend test implemented in PLINK and allelic odds ratios with 95 % confidence intervals (CI) calculated in STATA 9.2.
Of the 150 SNPs tested, 9 were found to be significantly associated (p-trend <= 0.05) with MTX response and 2 with MTX related AE. Interestingly 3 of these (rs12995526, rs7563206 and rs16853834) were found in the 5-aminoimidazole-1394-carcoxamide ribonucleotide transformylase (ATIC) gene which encodes an enzyme that is important in the de novo purine synthesis pathway. Individuals carrying these SNPs had an increased risk of poor response to MTX (OR 1.48, 95%CI (1.012.17), OR 1.47, 95%CI (1.002.17) and OR 1.47 95% CI (1.012.76) respectively). Other associations included 6 SNPs in the SLC19A1 gene (rs11702425, rs2838956, rs7499, rs2274808, rs9977268, rs7279445) all conferring an increased risk of poor response to MTX and two SNPs in the DHFR gene (rs12517451, rs10072026) were associated with AE. In addition there were a further 2 SNPs in the FPGS gene associated with AE under a recessive model (rs1054774, rs4451422) and 1 additional SNP in the ATIC gene approaching statistical significance (rs4673990) (p-trend<0.1) warranting further investigation.
Genetic variations in a number of key MTX pathway genes have been found to be significantly associated with MTX response and AE in RA patients. Further studies will be required to validate these findings. If confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.
To cite this abstract, please use the following information:
Owen, Sally-Anne, Eyre, Stephen, Martin, Paul, Hider, Samantha, Bruce, Ian N., Barton, Anne, et al; Genetic Polymorphisms in Key Methotrexate (MTX) Pathway Genes Associated with Response to MTX Treatment in Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1394