Association between SLCO1A2 genetic variation and methotrexate toxicity in human rheumatoid arthritis treatment

J Biochem Mol Toxicol. 2020 Aug;34(8):e22513. doi: 10.1002/jbt.22513. Epub 2020 Apr 18.

Abstract

Methotrexate (MTX), one of the important disease-modifying anti-rheumatic drugs, is the first-line drug for rheumatoid arthritis (RA) treatment. However, its adverse drug effects (ADEs) often lead to the abortion of MTX therapy. Human organic anion-transporting polypeptide 1A2 (OATP1A2, also referred as OATP-A or OATP1) encoded by SLCO1A2 gene is an important isoform of the solute carrier transporter (SLC) family. It is known to participate in the cellular uptake of MTX. In our previous study, we identified four OATP1A2 natural variants (E184K, D185N, T259P, and D288N) with impaired MTX uptake activity. This study aimed to evaluate the association of the SLCO1A2 genetic variations encoding these OATP1A2 variants and MTX-related toxicity in RA patients. A total of 60 RA patients were genotyped for these four polymorphisms (G550A, G553A, A775C, and G862A). The association between SLCO1A2 genetic variations and MTX toxicity was analyzed by binary logistic regression analysis. Single nucleotide polymorphisms (SNPs) analysis revealed that A775C and G862A SNPs were not detected in RA patients enrolled in this study, and the presence of 550AA genotype was associated with a high risk of MTX ADEs. Haplotype analysis revealed that H3 (H3 = AG) showed a high risk of MTX ADEs. Furthermore, there was a significant association of 550AA genotype and impaired MTX disposition, which might be the cause of the increased incidence of MTX ADEs in RA patients. Therefore, genetic variations in SLCO1A2 gene are risk factors for MTX toxicity and its information contributes to the prediction of MTX-related toxicity in RA treatment.

Keywords: SLCO1A2; genetic variation; methotrexate toxicity; rheumatoid arthritis.

Publication types

  • Clinical Trial

MeSH terms

  • Aged
  • Amino Acid Substitution
  • Arthritis, Rheumatoid* / drug therapy
  • Arthritis, Rheumatoid* / genetics
  • Female
  • Humans
  • Male
  • Methotrexate* / administration & dosage
  • Methotrexate* / adverse effects
  • Middle Aged
  • Mutation, Missense*
  • Organic Anion Transporters / genetics*
  • Polymorphism, Single Nucleotide*

Substances

  • Organic Anion Transporters
  • SLCO1A2 protein, human
  • Methotrexate