Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Ann Rheum Dis. 2019 Aug;78(8):1055-1061. doi: 10.1136/annrheumdis-2018-214877. Epub 2019 Apr 29.
We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response.
We studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation.
We detected a statistically significant association between Δ SJC and the RA score at the locus (p=0.0004) and an inverse association between Δ SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance.
The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and pathways could be relevant for targeting drug therapy.
我们试图通过考虑与相关特征相关的已知遗传易感性基因座，来确定 TNF 抑制剂 (TNFi) 治疗类风湿关节炎 (RA) 反应的遗传效应是否可以局部化，并评估这些遗传基因座对药物反应分层的有用性。
我们研究了 2938 名基因分型个体中 TNFi 反应（通过肿胀关节计数 (ΔSJC) 和红细胞沉降率 (ΔESR) 的变化来量化）与基于全基因组关联研究汇总统计数据构建的基因座特异性评分之间的关系：37 个 RA 评分；19 个免疫细胞特征评分；93 个基因表达或甲基化评分，这些基因的转录水平与药物反应之间存在先前报道的关联。通过交叉验证在惩罚回归模型中评估多变量关联。
我们在 基因座检测到 ΔSJC 与 RA 评分之间存在统计学显著关联（p=0.0004），以及 ΔSJC 与 CD4 T 细胞上 CD39 表达评分之间存在负相关（p=0.00005）。先前报道的调节性 T 细胞上 CD39 表达与甲氨蝶呤反应之间的关联方向相反。在同时接受甲氨蝶呤治疗的分层分析中，联合治疗组的负相关更强，而 TNFi 单药治疗组的负相关减弱。总体而言，从基因型评分预测 TNFi 反应的能力有限，模型解释的表型方差不足 1%。
与 CD39 特征的关联难以解释，因为 RA 患者通常在对甲氨蝶呤无反应后才开始接受 TNFi 治疗。CD39 和 途径可能与靶向药物治疗有关。
