骨吸收相关基因作为肿瘤坏死因子-α拮抗剂治疗类风湿关节炎药敏基因的研究

Tumor necrosis factor (TNF) –α blockers have been widely used in rheumatoid arthritis (RA) treatment, but 1/3 of patients have an impaired response to it and the lack of biomarkers to accurately predict the response. To find susceptibility genes associated with the response is very important for RA to choose rational drugs and realize individualized medical treatment. Based on our previous study, we proposed hypothesis that genes related to bone resorption are associated with the drug treatment response. In our study, the enrolled patients are RA who accepted TNF-α blockers treatment for 6 months and they will be divided into good responders, moderate responders and non-responders according to their response to the drug. Research is divided into 3 stages, the first is to select candidate genes from a large quantity of genes related to bone resorption by various gene analysis methods. Second in a small case-control study (n = 36), using targeted sequencing to capture the candidate genes region and followed by exome sequencing in different response groups, to find single nucleotide polymorphism (SNP) and it’s genes who are associated with the drug treatment response. Third, expanding the sample size (n=200) in each group, using mass spectrometry to validate the preliminary susceptibility gene found in stage 2 and eventually determine the real susceptibility genes.

肿瘤坏死因子（TNF）-α拮抗剂已广泛应用于类风湿关节炎（RA）的治疗，但有1/3的病人对该药无反应或反应差，找到该药治疗RA的药敏基因对指导合理用药，实现RA个体化治疗有重要意义。本研究基于前期的研究成果拟从骨吸收相关基因中寻找TNF-α拮抗剂治疗RA的药敏基因。研究对象为接受TNF-α拮抗剂治疗6个月的RA患者，按其治疗反应分为反应良好组、中度反应组及无反应组。研究分为三个阶段，第一是通过多种分析手段从大量骨吸收相关基因中选出候选基因，确定候选基因区域；第二进行小样本的病例对照研究（每组36例），采用目标区域捕获技术捕获样本DNA的候选基因区域，随后进行外显子测序，通过对比分析不同治疗反应组的测序数据初步确定差异单核苷酸多态性（SNP）及其相关药敏基因；第三扩大各组样本量（每组200例），采用质谱分析技术对初步确定的药敏基因进行验证，最终找到TNF-α拮抗剂治疗RA的药敏基因。

肿瘤坏死因子（TNF）-α拮抗剂已广泛应用于类风湿关节炎（RA）的治疗，但有1/3的病人对该药无反应或反应差，找到该药治疗RA的药敏基因对指导合理用药，实现RA个体化治疗有重要意义。本研究基于前期的研究成果拟从骨吸收相关基因中寻找TNF-α拮抗剂治疗RA的药敏基因。研究对象为接受TNF-α拮抗剂治疗6个月的RA患者，按其治疗反应分为反应良好组、中度反应组及无反应组。研究分为三个阶段，第一是通过多种分析手段从大量骨吸收相关基因中选出候选基因，确定候选基因区域；第二进行小样本的病例对照研究（每组48例），采用目标区域捕获技术捕获样本DNA的候选基因区域，随后进行外显子测序，通过对比分析不同治疗反应组的测序数据初步确定差异单核苷酸多态性（SNP）及其相关药敏基因；第三扩大各组样本量（每组200例），采用质谱分析技术对初步确定的药敏基因进行验证，最终找到了rs869320688、rs869320689、rs869320754、rs121908655等位点的基因型与TNF-α拮抗剂对RA的治疗疗效具有相关性。