Genetic Variation in the SLC19A1 gene and Methotrexate Toxicity in Rheumatoid Arthritis Patients

• Published in: Pharmacogenomics Vol. 13; no. 14; pp. 1583 - 1594
• Main Authors: Bohanec Grabar, Petra, Leandro-García, Luis J, Inglada-Pérez, Lucía, Logar, Dušan, Rodríguez-Antona, Cristina, Dolžan, Vita
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.11.2012
• Subjects: Aged; Analysis; Antirheumatic Agents - administration & dosage; Antirheumatic Agents - toxicity; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Biomarkers, Pharmacological; Cell Line; Drug therapy; Drugs; Female; Genetic aspects; Genetic Association Studies; Haplotypes; Health aspects; Humans; Linkage Disequilibrium; Male; Methotrexate; Methotrexate - administration & dosage; Methotrexate - toxicity; Middle Aged; Polymorphism, Single Nucleotide; Reduced Folate Carrier Protein - genetics; Rheumatoid arthritis; Single nucleotide polymorphisms; Slovenia; Spain
• ISSN: 1462-2416; 1744-8042; 1744-8042
• DOI: 10.2217/pgs.12.150

We investigated the clinical relevance of SLC19A1 genetic variability for methotrexate (MTX) toxicity in rheumatoid arthritis patients using a haplotype-based approach. Two hundred and twelve unrelated rheumatoid arthritis patients and 89 lymphoblastoid cell lines were used to investigate the effect of SLC19A1 SNPs and haplotypes on MTX adverse events and treatment discontinuation. Two putatively functional SNPs in high linkage disequilibrium, rs1051266 and rs1131596, were associated with protection (hazard ratio: 0.33; 95% CI: 0.16-0.69; adjusted p = 0.021 and hazard ratio: 0.38; 95% CI: 0.17-0.27; adjusted p = 0.021, respectively) of discontinuation of MTX treatment owing to toxicity. These SNPs were also associated with protection from infections. SLC19A1 haplotype analysis found significant associations with MTX discontinuation owing to toxicity (p = 0.025). Quantification of SLC19A1 mRNA in cell lines suggested that rs1131596 was not a major causal variant. Individual SNP and haplotype analyses suggest that rs1051266 could be a functional variant altering MTX toxicity; however, validation in independent studies is needed.