ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients.
OBJECTIVE
Methotrexate (MTX) is most widely used for the treatment of rheumatoid arthritis (RA). However, it has certain drawbacks with regard to individual differences in its therapeutic effects as well as the differences in the patients' response to MTX therapy. We investigated whether multi-drug resistance-1 (ABCB1) C3435T, reduced folate carrier-1 (RFC1) G80A, 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) C347G and a 6bp-deletion polymorphism in the 3'-untranslated region of the thymidylase synthase (TYMS) gene are predictive of MTX sensitivity and its adverse effects.


METHODS
Patients whose last maintenance dosage of MTX was <or= 6 mg/week were regarded as responders, while patients whose last maintenance dosage of MTX was > 6 mg/week or those in whom MTX therapy was changed due to poor response to MTX were regarded as non-responders. The data of 124 RA patients who had received MTX treatment were retrospectively analyzed for polymorphisms in the ABCB1, RFC1, ATIC and TYMS genes, MTX sensitivity and MTX toxicity.


RESULTS
There were no significant differences in MTX sensitivity among the genotypes of RFC1, ATIC and TYMS genes. ABCB1 3435TT cases included statistically significantly more non-responders than 3435CC cases according to univariate analysis (crude odds ratio (OR) = 8.91, p = 0.001) and multivariate analysis (adjusted OR = 8.78, p = 0.038). There were no significant differences in MTX toxicity among the genotypes of all the genes.


CONCLUSIONS
These results suggested that the genetic diagnosis of ABCB1 C3435T can be applied to determine MTX sensitivity for the treatment of RA patients. However, further pharmacokinetics studies are required in this regard.
Takatori
R
R
Dept. of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. r-taka@koto.kpu-m.ac.jp
Takahashi
K A
KA
Tokunaga
D
D
Hojo
T
T
Fujioka
M
M
Asano
T
T
Hirata
T
T
Kawahito
Y
Y
Satomi
Y
Y
Nishino
H
H
Tanaka
T
T
Hirota
Y
Y
Kubo
T
T
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D005838:Genotype; D006304:Health Status; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics; D007596:Joints / Q000503:physiopathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D009709:Nucleotide Deaminases / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018501:Antirheumatic Agents; D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D027361:Organic Anion Transporters; C120043:SLC19A2 protein, human; C113120:inosine monophosphate synthase; D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D008727:Methotrexate