Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Genetic Polymorphisms in Key Methotrexate (MTX) Pathway Genes Associated with Response to MTX Treatment in Juvenile Idiopathic Arthritis
Hinks1, Anne, Moncrieffe2, Halima, Martin1, Paul, Lal1, S.D., Ursu2, Simona, Kassoumeri2, Laura, Wedderburn2, L. R.
The primary disease modifying therapy in use in juvenile idiopathic arthritis (JIA) is methotrexate (MTX). However, around 35% of children will fail to respond to MTX treatment. The main determinates of MTX response in JIA remain unclear although evidence suggests there may be a genetic component. Genes within the MTX metabolic pathway represent good candidates as predicators of response.
To investigate the effect of SNPs across 13 MTX pathway genes on the efficacy of MTX in patients with JIA.
Subjects were recruited from the SPARKS Childhood Arthritis Response to Medication Study (SPARKS CHARMS) whose response to MTX had been determined over a 6 month period. The cohort included 314 UK Caucasian children whose response was measured using the ACR Paediatric response criteria. Patients were included if they were either ACR Ped 70 (n=72) or non-responders (n=51). Tagging SNPs were selected for ABCG2, ADORA2A, 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 giving an average coverage after QC of >89%. Genotyping was performed using the Sequenom iPlex® MassARRAY platform. Genotype frequencies were compared between non-responders and responders (ACR70) using the trend test implemented in PLINK and allelic Odds ratios with 95 % confidence intervals calculated in STATA 9.2.
Of the 193 SNPs tested, 3 were found to be significantly associated (pTREND <= 0.05) with MTX response. Interestingly 2 of these (rs12995526 & rs4673990) were found in the 5-aminoimidazole-4-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 not responding to MTX (OR 1.79, 95% CI 1.073.00 and OR 1.69, 95% CI 1.012.83, respectively). Another association was found in the ITPA gene (rs2295553) which again conferred an increased risk of not responding to MTX (OR 1.73, 95%CI 1.032.89). In addition there were a further 10 SNPs with a trend towards association (p<0.1) in the genes encoding MTHFR, AMPD1, ATIC, DHFR, SHMT1, ITPA and SLC19A1, which are worthy of further follow up.
Genetic variations in a number of key MTX pathway genes have been found to be significantly associated with MTX response in JIA 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 JIA..
This study was supported by SPARKS UK, the Big Lottery Fund and the arthritis research campaign.
To cite this abstract, please use the following information:
Hinks, Anne, Moncrieffe, Halima, Martin, Paul, Lal, S.D., Ursu, Simona, Kassoumeri, Laura, et al; Genetic Polymorphisms in Key Methotrexate (MTX) Pathway Genes Associated with Response to MTX Treatment in Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :622