title: Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice.
abstract: BACKGROUND
  For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized adverse events.
  
  
  METHODS
  We conducted retrospective studies to validate our previous three different results about the association between adverse events or efficacy of two different disease-modifying antirheumatic drugs and genomic variations. Association between single nucleotide polymorphisms in N-acetyltransferase 2 gene (NAT2) and adverse events by sulfasalazine and association between C677T or A1298C in 5,10-methylenetetrahydrofolate reductase gene (MTHFR) and responses to methotrexate were examined.
  
  
  RESULTS
  Patients without the wild-type haplotype at NAT2 were more likely to suffer from overall adverse events [n=186, P=0.001, relative risk (RR) 3.31, 95% confidence interval (CI) 1.76-6.22] and severe adverse events (P=0.015, RR 24.6, 95% CI 2.37-254.53) by sulfasalazine. Patients with the T allele at C677T in MTHFR were more susceptible to overall adverse events (n=156, P=0.003; RR 2.4, 95% CI 1.29-4.55) while patients with the C allele at A1298C were less likely to be treated with a higher dose (>6 mg/week) of methotrexate in one year of treatment (n=159, P=0.008, RR 1.84, 95% CI 1.12-3.01). In all three association studies, the results were essentially the same as previously reported.
  
  
  CONCLUSIONS
  As three studies on the associations between genomic variations and adverse events or efficacy of two different disease-modifying antirheumatic drugs were replicated, the usefulness of the tests is worth being tested in clinical practice.
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-0054, Japan. amtanigu@ior.twmu.ac.jp
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Wako
authors.initials: W
authors.lastname: Urano
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tanaka
authors.forename: Shiori
authors.initials: S
authors.lastname: Furihata
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kamitsuji
authors.forename: Eisuke
authors.initials: E
authors.lastname: Inoue
authors.forename: Mariko
authors.initials: M
authors.lastname: Yamanaka
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012189:Retrospective Studies; D012460:Sulfasalazine / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D018501:Antirheumatic Agents; D012460:Sulfasalazine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D008727:Methotrexate