The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis
The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis
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DOI：
10.1002/art.39966
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发表时间：
2017-04-01
影响因子：
13.3
通讯作者：
Raychaudhuri, Soumya
中科院分区：
文献类型：
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作者：
Cui, Jing;Diogo, Dorothee;Raychaudhuri, Soumya
客观的。在许多类风湿性关节炎 (RA) 患者中，疾病可以通过抗肿瘤坏死因子（抗 TNF）生物疗法得到控制。然而，在相当多的患者中，该疾病对抗 TNF 治疗没有反应。我们进行本研究是为了检验罕见和低频遗传变异可能影响抗 TNF 治疗反应的假设。方法。我们对 1,094 名接受抗 TNF 治疗的欧洲血统 RA 患者的 750 个基因的编码区进行了测序。经过质量控制，690 个基因被纳入分析。我们应用单变异关联和基于基因的关联测试来识别与抗 TNF 治疗反应相关的变异。此外，鉴于 TNF 的关键机制作用，我们对 27 个 TNF 通路基因进行了基因集分析。结果。我们鉴定了 14,420 个功能变体，其中 6,934 个被预测为非同义变体，其中 2,136 个被进一步预测为“有害”。尽管该研究效果良好，但没有任何单一变异或基因显示出整个研究范围内与疾病活动或欧洲抗风湿病联盟反应结果变化的显着关联。有趣的是，我们观察到 27 个基因中的 3 个具有名义关联信号（P < 0.05），它们参与 TNF 信号通路。然而，当我们根据关联 P 值排序进行严格的基因集富集分析时，我们没有观察到 TNF 途径涉及的基因关联富集的证据（P 富集 = 0.15，基于表型排列）。结论。我们的研究结果表明 TNF 信号传导中存在罕见且低频的蛋白质编码变异\
Objective. In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment.Methods. We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes.Results. We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (P-enrichment = 0.15, based on phenotype permutations).Conclusion. Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling\