Avila-Pedretti Gabriela, Tornero Jesús, Fernández-Nebro Antonio, Blanco Francisco, González-Alvaro Isidoro, Cañete Juan D, Maymó Joan, Alperiz Mercedes, Fernández-Gutiérrez Benjamín, Olivé Alex, Corominas Héctor, Erra Alba, Aterido Adrià, López Lasanta María, Tortosa Raül, Julià Antonio, Marsal Sara
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
Hospital Universitario De Guadalajara, Rheumatology Department, Guadalajara, Spain.
PLoS One. 2015 Apr 7;10(4):e0122088. doi: 10.1371/journal.pone.0122088. eCollection 2015.
Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response.
A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy.
We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042).
In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.
抗TNF疗法在类风湿关节炎（RA）的治疗中疗效显著，但25% - 30%的患者并未表现出明显的临床反应。越来越多的证据表明，Fc受体FCGR2A的基因变异与抗TNF治疗的反应相关。我们旨在验证西班牙人群患者队列中的这种基因关联，并识别与FCGR2A功能相关且也与抗TNF反应相关的新基因。
共纳入348例接受抗TNF治疗的RA患者，并对FCGR2A多态性rs1081274进行基因分型。在12周时确定治疗反应，并对每种抗TNF药物（英夫利昔单抗、依那西普和阿达木单抗）进行整体及独立的关联测试。利用从RA患者滑液中获得的巨噬细胞的基因表达谱，我们寻找与FCGR2A表达高度相关的基因。从每个候选基因中选择标签单核苷酸多态性（Tag SNPs），并测试其与治疗反应的关联。
我们发现FCGR2A与阿达木单抗的反应之间存在显著关联（P = 0.022）。分析抗环瓜氨酸肽（anti - CCP）阳性RA患者亚组（78%）时，我们还发现FCGR2A与英夫利昔单抗的反应之间存在显著关联（P = 0.035）。DHX32和RGS12是RA滑液巨噬细胞中与FCGR2A表达最一致相关的基因（P < 0.001）。我们发现DHX32的基因变异（rs12356233，校正后P = 0.019）之间存在显著关联，RGS12与阿达木单抗的反应之间存在名义上的显著关联（rs4690093，未校正P = 0.040）。在抗CCP阳性患者组中，我们还发现RGS12与英夫利昔单抗的反应之间存在名义上的显著关联（rs2857859，未校正P = 0.042）。
在本研究中，我们在独立人群中验证了FCGR2A的关联，并识别出与RA中抗TNF治疗反应相关的新基因。
