Moving toward personalized medicine in rheumatoid arthritis: SNPs in methotrexate intracellular pathways are associated with methotrexate therapeutic outcome.
Evaluate the potential of selected SNPs as predictors of methotrexate (MTX) therapeutic outcome.



In total, 35 SNPs in 14 genes involved in MTX intracellular pathways and Phase II reactions were genotyped in 233 rheumatoid arthritis (RA) patients treated with MTX. Binary logistic regressions were performed by genotype/haplotype-based approaches. Non-Response- and Toxicity-Genetic Risk Indexes (Non-RespGRI and ToxGRI) were created.



MTX nonresponse was associated to eight genotypes and three haplotypes: MTHFR rs1801131 AA and rs1801133 TT; MS rs1805087 AA; MTRR rs1801394 A carriers; ATIC rs2372536 C carriers, rs4673993 T carriers, rs7563206 T carriers and rs12995526 T carriers; CC for GGH rs3758149 and rs12681874; CGTTT for ATIC combination 1; and CTTTC for ATIC combination 2. From overall Non-RespGRI patients with indexes 6-8 had more than sixfold increased risk for MTX nonresponse than those patients with indexes 0-5. MTX-related toxicity was associated to five genotypes and two haplotypes: ATIC rs2372536 G carriers, rs3821353 T carriers, rs7563206 CC and rs12995526 CC; ADORA2A rs2267076 T; CTTCC for ATIC combination 1; and TC for ADORA2A rs2267076 and rs2298383. From overall ToxGRI, patients with indexes 3-4 had more than sevenfold increased risk for MTX-related toxicity than those patients with indexes 1-2.



Genotyping may be helpful to identify which RA patients will not benefit from MTX treatment and, consequently, important to personalized medicine in RA. Nevertheless, further studies are required to validate these findings.
CESPU, Institute of Research & Advanced Training in Health Sciences & Technologies, Department of Pharmaceutical Sciences, Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal.|Molecular Oncology & Viral Pathology Group - Research Center, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.|Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
Aurea
A
Lima
Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.|Rheumatology Department of São João Hospital Center, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Miguel
M
Bernardes
Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.|Experimental Pathology & Therapeutics Group - Research Center, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
Rita
R
Azevedo
CESPU, Institute of Research & Advanced Training in Health Sciences & Technologies, Department of Pharmaceutical Sciences, Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal.
Vitor
V
Seabra
Molecular Oncology & Viral Pathology Group - Research Center, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.|Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.|Research Department-Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação, 6657, 4200-177 Porto, Portugal.
Rui
R
Medeiros
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine
D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate
genetic risk index; methotrexate; personalized medicine; pharmacogenomics; polymorphisms; response; rheumatoid arthritis; therapeutic outcome; toxicity