Background Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment with a wide variety of clinical responses1. Therefore, studies have been conducted to help elucidate the potential role of genetic polymorphisms in MTX influx and efflux transporters (solute carriers – SLC and ATP-binding cassette – ABC, respectively) as well as in the development of MTX-related gastrointestinal toxicity (MTX-GastroTox)2.
Objectives We aimed to evaluate the influence of several single nucleotide polymorphisms (SNP) in genes that codify to MTX transporters with the occurrence of MTX-GastroTox in Portuguese RA patients.
Methods A total of 233 RA patients were included in the study and genotyped by Sequenom MassARRAY® for 20 SNPs (SLC16A7, SLC19A1, SLC22A6, SLC22A11, SLC46A1, SLCO1B1, ABCB1, ABCC1, ABCC2 and ABCG2). Binary logistic regression analyses were performed and adjusted to possible confounder variables (related to patient, disease and treatment). Haplotype analysis was used to test SNPs that revealed to be statistically significant and a risk index for MTX-GastroTox was created.
Results In this population, SLC19A1 rs7499 G carriers (p=0.013, OR=5.46), SLC19A1 rs1051266 G carriers (p=0.039, OR=2.94), SLCO1B1 rs4149056 T carriers (p=0.039, OR=3.13) and ABCG2 rs13120400 C carriers (p=0.042, OR=2.26) were associated with increased risk for MTX-GastroTox. SLC19A1 rs7499 and rs1051266 revealed to be in linkage disequilibrium (p<0.001, D'=0.81) with the AA haplotype being associated with MTX-GastroTox protection (p=0.024, OR=0.45). In addition, the risk index revealed that patients with 3 or 4 risk variants (SLC19A1 rs7499 GG, SLC19A1 rs1051266 GG, SLCO1B1 rs4149056 TT and ABCG2 rs13120400 CC) had a 13-fold increased risk for MTX-GastroTox (p=0.006, OR=13.4).
Conclusions SLC19A1, SLCO1B1 and ABCG2 genotyping may be a useful tool for assist clinicians to identify patients at higher risk for developing gastrointestinal toxicity related with MTX treatment.
Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bulletin of the NYU hospital for joint diseases. [Review]. 2007;65(3):168-73.
Lima A, Bernardes M, Sousa H, Azevedo R, Costa L, Ventura F, et al. SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients. Pharmacogenomics. 2013:1-14
Acknowledgements The authors wish to acknowledge to Fundação para a Ciência e Tecnologia (FCT) for the Doctoral Grant (SFRH/BD/64441/2009) for Aurea Lima and also to the nursing service of Rheumatology Day Hospital of São João Hospital Center and the clinicians from the Rheumatology Department of São João Hospital Center.
Disclosure of Interest None declared