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Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate

Stamp, Lisa K.a c; Chapman, Peter T.c; O'Donnell, John L.c; Zhang, Meid; James, Jillc; Frampton, Christophera; Barclay, Murray L.a d; Kennedy, Martin A.b; Roberts, Rebecca L.e

Pharmacogenetics and Genomics: June 2010 - Volume 20 - Issue 6 - p 367-376
doi: 10.1097/FPC.0b013e3283398a71

Objectives 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.

Methods 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.

Results 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).

Conclusion 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:

Received 11 November 2009 Accepted 9 March 2010

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© 2010 Lippincott Williams & Wilkins, Inc.