SLC19A1, SLC46A1 and SLCO1B1 Polymorphisms as Predictors of Methotrexate-Related Toxicity in Portuguese Rheumatoid Arthritis Patients

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Lima, A (Author) Other; Bernardes, M (Author) Other; Azevedo, R (Author) Other; Monteiro, J (Author) Other; Sousa, H (Author) Other; Rui Medeiros (Author) ICBAS; Seabra, V (Author) Other

Journal

Title: Toxicological Sciences

Vol. 142

Pages: 196-209

ISSN: 1096-6080

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 44 Citations

Scopus - 51 Citations

Other information

Authenticus ID: P-00A-1T7

DOI: 10.1093/toxsci/kfu162

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14