DANBIO Registry and Department of Rheumatology, Copenhagen University Hospital at Glostrup, Copenhagen, Denmark.
PLoS One. 2012;7(6):e38539. doi: 10.1371/journal.pone.0038539. Epub 2012 Jun 7.
TNFα inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNFα inhibitors in patients with rheumatoid arthritis (RA).
In the DANBIO Registry we identified 237 TNFα inhibitor naïve patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n=160), adalimumab (n=56) or etanercept (n=21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fisher's exact test. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR=4.43, 95% CI: 1.99-10.09, p=7.211×10(-5)) and with EULAR good response vs. moderate/no response (OR=4.54, 95% CI: 2.29-8.99, p=3.336×10(-6)). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR=4.01, 95% CI: 1.92-8.49, p=5.067×10(-5)).
Genetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA.
TNFα 抑制剂治疗极大地改善了类风湿关节炎患者的治疗效果，但至少有 30%的患者对此没有反应。我们旨在研究与类风湿关节炎（RA）患者对 TNFα 抑制剂反应相关的插入和缺失（INDELs）。
在 DANBIO 登记处，我们确定了 237 名 TNFα 抑制剂初治的 RA 患者（81%为女性；中位年龄 56 岁；疾病持续时间 6 年），他们于 1999 年至 2008 年期间根据国家治疗指南接受了英夫利昔单抗（n=160）、阿达木单抗（n=56）或依那西普（n=21）治疗。在第 26 周使用 EULAR 反应标准评估临床反应。根据文献，我们使用 GeneVa®（Compugen）在人类基因组中 350,000 个遗传变异的数据库中选择了 213 个与 RA 和治疗反应相关的 INDELs。通过聚合酶链反应（PCR）扩增基因组片段，并通过 Sanger 测序或片段分析进行基因分型。我们使用 Fisher's 确切检验测试了基因型与 EULAR 良好反应与无反应、EULAR 良好反应与中度/无反应之间的关联。在基线时，DAS28 的中位数为 5.1。在第 26 周时，68 名（29%）患者为 EULAR 良好反应者，81 名（34%）和 88 名（37%）患者为中度和非反应者。CD6 基因内的 19 个碱基插入与 EULAR 良好反应与无反应（OR=4.43，95%CI：1.99-10.09，p=7.211×10(-5))和 EULAR 良好反应与中度/无反应（OR=4.54，95%CI：2.29-8.99，p=3.336×10(-6))相关。位于 syntaxin binding protein 6（STXBP6）内的微卫星与 EULAR 良好反应与无反应（OR=4.01，95%CI：1.92-8.49，p=5.067×10(-5))相关。
CD6 和 STXBP6 内的遗传变异可能影响 RA 患者对 TNFα 抑制剂的反应。
