title: The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients.
abstract: Some single-nucleotide polymorphisms (SNPs) might be predictive of methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA). The aim of this study was to determine whether SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene are predictive of MTX response. Comparison was made using EULAR response criteria and according to the change of DAS28 (∆DAS28) after a 6-month MTX treatment in RA patient cohort. The two SNPs C677T (rs1801133) and A1298C (rs1801131) have been genotyped. A total of 120 patients were enrolled in the study, and all of them fulfilled the American College of Rheumatology 1987 RA criteria and are currently or previously taking MTX oral treatment, either as a monotherapy (n = 65) or in a combination with other disease-modifying antirheumatic drugs (n = 55). Genotyping was performed using qPCR allelic discrimination. We did not found any association of C677T and A1298C genotypes with MTX treatment inefficacy in dominant model (OR 1.23, 95 % CI 0.57-2.65, P = 0.697; and OR 0.98, 95 % CI 0.47-2.14, P = 1.0, respectively), or in recessive and codominant models. However, when ∆DAS28 after a 6-month therapy was used as a measure of treatment efficacy, the 677CT and 1298AC genotypes were found to be significantly associated with less favorable response to MTX (P = 0.025 and P = 0.043, respectively). In addition, even lower ∆DAS28 was determined for double-mutated 677CT-1298AC heterozygotes. It means that a synergistic effect of 677CT and 1298AC genotypes was observed. Nevertheless, the DAS28 baseline was lower here comparing to other genotypes. Unexpectedly, quite the opposite trend-i.e., better response to MTX-was found in genotypes 677CC-1298CC and 677TT-1298AA. It is an intriguing finding, because these double-mutated homozygotes are known for their low MTHFR-specific activity. Global significance was P = 0.013, η (2) = 0.160-i.e., large-size effect. Thus, our data show greater ability of 677CC-1298CC and 677TT-1298AA genotypes to respond to MTX treatment.
authors.affiliation: Faculty of Medicine and University Hospital, 2nd Department of Internal Medicine - Gastroenterology, Charles University in Prague, Sokolska 581, 500 05, Hradec Kralove, Czech Republic, soukutom@seznam.cz.
authors.forename: Tomas
authors.initials: T
authors.lastname: Soukup
authors.forename: Martin
authors.initials: M
authors.lastname: Dosedel
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
authors.forename: Jana
authors.initials: J
authors.lastname: Nekvindova
authors.forename: Ivan
authors.initials: I
authors.lastname: Barvik
authors.forename: Iva
authors.initials: I
authors.lastname: Bubancova
authors.forename: Petr
authors.initials: P
authors.lastname: Bradna
authors.forename: Ales Antonin
authors.initials: AA
authors.lastname: Kubena
authors.forename: Alejandro Fernández
authors.initials: AF
authors.lastname: Carazo
authors.forename: Tomas
authors.initials: T
authors.lastname: Veleta
authors.forename: Jiri
authors.initials: J
authors.lastname: Vlcek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D003430:Cross-Sectional Studies; D018153:Czech Republic; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate