title: SLC19A1, SLC46A1 and SLCO1B1 polymorphisms as predictors of methotrexate-related toxicity in Portuguese rheumatoid arthritis patients.
abstract: Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment showing a wide toxicity profile. This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding for MTX transporters with the occurrence of MTX-related toxicity (overall and gastrointestinal). A total of 233 Portuguese RA patients were genotyped for 23 SNPs. Haplotype analyses were performed and a toxicogenetic risk index (TRI) was created for SNPs that revealed to be statistically significant. Regarding MTX overall toxicity, an increased risk was associated to SLC19A1 rs7499 G carriers (p = 0.017), SLC46A1 rs2239907 GG (p = 0.030) and, SLCO1B1 rs4149056 T carriers (p = 0.040) and TT (p = 0.019). TRI revealed that patients with Index 3 were 18-fold more likely to present an adverse drug reaction when compared to those with Index 1 (p = 0.001). For MTX gastrointestinal toxicity, results demonstrated an increased risk associated with SLC19A1 rs7499 G carriers (p = 0.012) and GG (p = 0.045), SLC19A1 rs1051266 G carriers (p = 0.034), SLC19A1 rs2838956 A carriers (p = 0.049) and, SLCO1B1 rs4149056 T carriers (p = 0.042) and TT (p = 0.025). Haplotype analyses showed association between GGAG haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity (p = 0.029). TRI revealed that patients with Index 4 were 9-fold more likely to present a gastrointestinal disorder when compared to those with Index 1 (p = 0.020). This study demonstrated that SLC19A1, SLC46A1 and SLCO1B1 genotypes may help to identify patients with increased risk of MTX-related overall toxicity and that SLC19A1 and SLCO1B1 genotypes, and SLC19A1 haplotypes may help to identify patients with increased risk of MTX-related gastrointestinal toxicity.
authors.affiliation: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal aurea.lima@iscsn.cespu.pt.
authors.forename: Aurea
authors.initials: A
authors.lastname: Lima
authors.affiliation: 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.
authors.forename: Miguel
authors.initials: M
authors.lastname: Bernardes
authors.affiliation: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Azevedo
authors.affiliation: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Monteiro
authors.affiliation: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Sousa
authors.affiliation: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal Research Department-Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação, 6657, 4200-177 Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal.
authors.forename: Vítor
authors.initials: V
authors.lastname: Seabra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects; D006239:Haplotypes; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D058979:Proton-Coupled Folate Transporter / Q000235:genetics*; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D018501:Antirheumatic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D058979:Proton-Coupled Folate Transporter; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C505058:SLC46A1 protein, human; C503999:SLCO1B1 protein, human; D008727:Methotrexate
keywords: methotrexate; polymorphisms; rheumatoid arthritis; toxicity; toxicogenetic risk index; transporters