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首页> 外文期刊>Journal of biochemical and molecular toxicology >Association between SLCO1A2 genetic variation and methotrexate toxicity in human rheumatoid arthritis treatment
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Association between SLCO1A2 genetic variation and methotrexate toxicity in human rheumatoid arthritis treatment

机译：SLCO1A2遗传变异与人文类风湿性关节炎治疗中甲氨蝶呤毒性的关系

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摘要

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.
机译：甲氨蝶呤（MTX）是治疗类风湿性关节炎（RA）的一线药物，是重要的抗风湿药物之一。然而，其不良药物效应（ADEs）往往导致MTX治疗流产。SLCO1A2基因编码的人有机阴离子转运多肽1A2（OATP1A2，又称OATP-A或OATP1）是溶质载体转运体（SLC）家族的重要亚型。已知参与细胞对MTX的摄取。在我们之前的研究中，我们鉴定了四种MTX摄取活性受损的OATP1A2自然变异体（E184K、D185N、T259P和D288N）。本研究旨在评估编码这些OATP1A2变体的SLCO1A2基因变异与RA患者MTX相关毒性的相关性。共有60名RA患者对这四种多态性（G550A、G553A、A775C和G862A）进行了基因分型。采用二元逻辑回归分析SLCO1A2基因变异与MTX毒性之间的关联。单核苷酸多态性（SNPs）分析显示，在本研究登记的RA患者中未检测到A775C和G862A SNPs，550AA基因型的存在与MTX ADE的高风险相关。单倍型分析显示H3（H3=AG）显示出MTX ADEs的高风险。此外，550AA基因型与MTX处置受损显著相关，这可能是RA患者MTX ADE发病率增加的原因。因此，SLCO1A2基因的遗传变异是MTX毒性的危险因素，其信息有助于预测RA治疗中MTX相关的毒性。

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