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


CONCLUSIONS
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.
Stamp
Lisa K
LK
Department of Medicine, University of Otago, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz
Chapman
Peter T
PT
O'Donnell
John L
JL
Zhang
Mei
M
James
Jill
J
Frampton
Christopher
C
Barclay
Murray L
ML
Kennedy
Martin A
MA
Roberts
Rebecca L
RL
D000659:AMP Deaminase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D005287:Ferredoxin-NADP Reductase; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D008727:Methotrexate / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D011099:Polyglutamic Acid / Q000031:analogs & derivatives; D011110:Polymorphism, Genetic
C000715087:ABCC2 protein, human; D000089762:Multidrug Resistance-Associated Protein 2; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012696:Glycine Hydroxymethyltransferase; D000659:AMP Deaminase; D008727:Methotrexate