To determine whether genetic polymorphisms within the folate pathway are associated with red blood cell (RBC) methotrexate (MTX) polyglutamate concentrations, RBC folate concentrations and MTX efficacy/toxicity.
Disease activity in 200 rheumatoid arthritis patients on MTX was assessed by swollen and tender joint counts and Disease Activity Score 28. Genetic polymorphisms shown to have an effect on gene expression or protein function were examined.
RBC folate concentrations were significantly associated with MTHFR 677C>T (P=0.002), MTRR 66A>G (P<0.0001), MTHFD1 1958G>A (P=0.001) and SHMT 1420C>T (P=0.012), whereas no association of these polymorphisms with disease activity was observed. None of the polymorphisms tested predicted RBC MTX polyglutamate concentrations. There were weak associations between central nervous system adverse effects and AMPD1 34C>T (P=0.04) and between gastrointestinal adverse effects and MTHFD1 1958G>A (P=0.03) and ABCC2 IVS23+56T>C (P=0.045). There was a stronger association between any adverse effect and ABCG2 914C>A (P=0.004).
Although RBC folate concentrations are associated with genetic polymorphisms within the folate pathway, these variants do not predict disease activity. To accurately evaluate whether any polymorphisms are reliable predictors of MTX efficacy or toxicity, large prospective clinical trials are required. Furthermore, application of a genome-wide association strategy is likely to uncover novel predictors of MTX response.
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aDepartment of Medicine
bGene Structure and Function laboratory, Department of Pathology, University of Otago, Christchurch
Departments of cRheumatology, Immunology and Allergy
dClinical Pharmacology, Christchurch Hospital, Christchurch
eDepartment of Biochemistry, University of Otago, Dunedin, New Zealand
Correspondence to Lisa K. Stamp, MBChB, FRACP, PhD, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand
Tel: +64 3 364 0953; fax: +64 3 364 0935; e-mail: email@example.com
Received 11 November 2009 Accepted 9 March 2010
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