Association of dihydrofolate reductase (DHFR) -317AA genotype with poor response to methotrexate in patients with rheumatoid arthritis.
OBJECTIVE
Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumatoid arthritis (RA) may have great importance for optimising drug doses required for clinical benefit without toxicity. In a group of 125 RA patients treated with MTX we investigated whether selected polymorphisms in genes relevant for MTX action (aminoimidazole-4-carboxiamide ribonucleotide transformylase, ATIC, and dihydrofolate reductase, DHFR) modulate disease activity and/or have impact on therapy side effects.


METHODS
The efficacy of treatment was estimated both by the disease activity score in 28 joints (DAS28), based on EULAR criteria, and relative DAS28 (rDAS28) score. Adverse drug events (ADEs) were also recorded. RA patients were genotyped using the PCR-RFLP method, followed by an association study between ATIC -129T>G, DHFR -216T>C and DHFR -317A>G polymorphisms and the efficacy and toxicity of MTX.


RESULTS
According to the EULAR response criteria, 96 RA patients (76.8%) were classified as responders (good/moderate response) and 29 (23.2%) as non-responders (poor response). rDAS28 values ranged from -0.01 to 0.80 (mean value 0.31±0.19). Among 125 patients enrolled in this study 39 experienced at least one side effect. The DHFR -317AA genotype was associated with the less favourable response (reduction in rDAS28 score, p=0.05). None of the analysed polymorphisms was associated with MTX toxicity.


CONCLUSIONS
RA patients with DHFR-317AA genotype had less favourable response to MTX. Further studies in larger patient populations are necessary to confirm the relationship between the analysed polymorphisms and MTX treatment response.
Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69, Resavska Str., 11000 Belgrade, Serbia. veramilic@ptt.rs
Vera
V
Milic
Biljana
B
Jekic
Ljiljana
L
Lukovic
Vera
V
Bunjevacki
Jelena
J
Milasin
Ivana
I
Novakovic
Tatjana
T
Damnjanovic
Branka
B
Popovic
Nela
N
Maksimovic
Nemanja
N
Damjanov
Goran
G
Radunovic
Nada
N
Pejnovic
Maja
M
Krajinovic
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016009:Chi-Square Distribution; D004185:Disability Evaluation; D005260:Female; D005787:Gene Frequency; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D009709:Nucleotide Deaminases / Q000235:genetics; D018579:Patient Selection; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D055771:Serbia; D012720:Severity of Illness Index; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D018501:Antirheumatic Agents; D009097:Multienzyme Complexes; C113120:inosine monophosphate synthase; D013762:Tetrahydrofolate Dehydrogenase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D008727:Methotrexate