Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, NL 2300 RC Leiden, The Netherlands.
Pharmacogenomics. 2010 Feb;11(2):163-75. doi: 10.2217/pgs.09.139.
Clinical response to methotrexate (MTX) treatment differs among rheumatoid arthritis patients. Genetic variation can partly account for this phenomenon. In this study, functional polymorphisms in genes related to the mechanism of action of MTX or immunopathogenesis of rheumatoid arthritis were studied for association with treatment outcome in a Dutch cohort of patients with early rheumatoid arthritis. Furthermore, tests for replication of previous research on these genetic variants were performed according to reported end points.
MATERIALS & METHODS: Seven polymorphisms in seven genes were analyzed in 205 genotyped patients with active rheumatoid arthritis. All patients received standardized MTX treatment (< or =25 mg per week orally) combined with folic acid. MTX treatment outcome was evaluated by disease activity score criteria and adverse drug events. The following genetic variants were analyzed and correlated: ABCB1 3435C>T, ITPA IVS2 +21A>C, HLA-G (-14 bp >+14 bp), TGFB1 +869T>C and TLR4 +896A>G. In case of significant differences, regression analyses were applied. Since carriers of the minor alleles of the SNPs DHFR 829C>T and IMPDH2 +787C>T were not observed, no statistical analyses could be performed.
No significant associations or replications of these genetic variants with MTX efficacy were demonstrated. Regarding toxicity, patients carrying the ABCB1 3435T-allele and TLR4 +896G-allele were 2.5-times more likely to develop adverse drug events at 6 months (odds ratio: 2.6; 95% CI: 1.1-6.2, and odds ratio: 2.5; 95% CI: 1.1-6.1, respectively). Additionally, this chance increased almost fourfold in patients with the two unfavorable genotypes (odds ratio: 3.9; 95% CI: 1.5-10.3). However, none of these associations remained significant after correction for multiple testing (p < 0.004).
Our data indicate that MTX toxicity was potentially associated with ABCB1 3435C>T and TLR4 +896A>G. However, after correction, none of these associations remained significant. Furthermore, no significant associations or replications of these functional variants with efficacy were found.
甲氨蝶呤（MTX）治疗的临床反应在类风湿关节炎患者中存在差异。遗传变异在一定程度上可以解释这种现象。在这项研究中，研究了与 MTX 作用机制或类风湿关节炎免疫发病机制相关的基因中的功能性多态性，以与荷兰早期类风湿关节炎患者队列的治疗结果相关联。此外，根据报道的终点对这些遗传变异的先前研究进行了复制测试。
对 205 名活跃的类风湿关节炎患者进行了七种基因中七种基因的多态性分析。所有患者均接受标准化的 MTX 治疗（每周 <或= 25 毫克口服），同时服用叶酸。通过疾病活动评分标准和药物不良反应评估 MTX 治疗效果。分析并相关联以下遗传变体：ABCB1 3435C>T、ITPA IVS2 +21A>C、HLA-G（-14 bp >+14 bp）、TGFB1 +869T>C 和 TLR4 +896A>G。如果存在显着差异，则应用回归分析。由于未观察到 SNPs DHFR 829C>T 和 IMPDH2 +787C>T 的少数等位基因携带者，因此无法进行统计学分析。
没有证明这些遗传变异与 MTX 疗效之间存在显着关联或复制。关于毒性，携带 ABCB1 3435T-等位基因和 TLR4 +896G-等位基因的患者在 6 个月时发生药物不良反应的可能性增加了 2.5 倍（优势比：2.6；95%置信区间：1.1-6.2，和优势比：2.5；95%置信区间：1.1-6.1）。此外，在具有两种不利基因型的患者中，这种机会增加了近四倍（优势比：3.9；95%置信区间：1.5-10.3）。然而，在进行多次测试校正后，这些关联均无统计学意义（p <0.004）。
我们的数据表明，MTX 毒性可能与 ABCB1 3435C>T 和 TLR4 +896A>G 相关。然而，在进行校正后，这些关联均无统计学意义。此外，没有发现这些功能变体与疗效之间存在显着关联或复制。
