糖皮质激素治疗SLE药物基因组学研究：HSP90家族基因变异及其与GR基因交互效应对糖皮质激素疗效的预测作用

Research results of pharmacogenomics can be rapidly applied to clinical individual therapy, and have shown great effect on some diseases. Currently, there were no research reports of pharmacogenomics of glucocorticoid (GC) in treatment of systemic lupus erythematosus (SLE). Glucocorticoid receptor (GR) and heat shock protein 90 (HSP90) play an important role in GC signaling pathway. We have analyzed whether genetic variation within GR gene are related to variability in the efficacy of GC, and, through the 12 weeks of treatment with GC in 200 SLE patients, found that GR gene variation can predict the efficacy of GC. Meanwhile, we preliminarily explored the prediction of part of HSP90 family gene variation to efficacy of GC in treatment of SLE. The results indicated that HSP90 family gene variation may affect efficacy of GC and there may be interaction effect between HSP90 gene and GR gene, which needs to be confirmed. At the same time, the 200 SLE patients were further follow-uped, and the results showed that some patients were easy to relapse between 18 and 24 weeks. In present study, 530 new-onset SLE patients will be enrolled. Prednisone is administered to patients for 24 weeks. SLE disease activity index (SLEDAI) is used to assess the efficacy of prednisone. SNaPshot technology is used to detect gene variation. The purpose of the present study is to explore the prediction of HSP90 family gene variation and HSP90-GR interaction effect to efficacy, includig relapse, of GC in treatment of SLE. The results of the present study are useful to guide clinical individual therapy in Chinese SLE patients.

药物基因组学成果可迅速应用于临床个体化治疗，在一些疾病中已经发挥出很大作用，目前未见糖皮质激素（GC）治疗系统性红斑狼疮（SLE）的药物基因组学研究报道。糖皮质激素受体（GR）和热休克蛋白90（HSP90）是介导GC作用最重要两个分子，课题组前期通过对200例SLE患者12周治疗随访发现GR基因变异可影响GC疗效；并初步探讨了部分HSP90基因变异对GC疗效的预测作用，发现HSP90基因变异可能影响GC疗效，并和GR基因存在交互效应，但有待扩大样本证实；同时课题组对前期入选患者进行了进一步随访，发现部分患者在18-24周间容易复发。本研究拟收集530例SLE新发病人，用泼尼松治疗24周，用SLEDAI评定疗效，用SNaPshot技术进行基因分型，深入探讨HSP90家族基因变异及其与GR基因交互效应对GC疗效（包括维持治疗时复发）的预测作用。本项目完成对指导SLE患者个体化用药具有重要意义。

证据表明糖皮质激素（GC）治疗系统性红斑狼疮（SLE）的疗效存在极大的个体化差异，这给SLE患者的合理用药带来困难。借助药物基因组学研究技术，基于遗传因素预测GC治疗SLE的疗效，在指导SLE合理用药中具有良好的应用前景。糖皮质激素受体（GR）和热休克蛋白90（HSP90）是介导GC发挥作用最重要两个分子，GR基因和HSP90基因（HSP90AA1、HSP90AA2、HSP90AB1、HSP90B1和TRAP1）变异可能是GC疗效存在个体化差异的原因之一。本课题收集了530例合格SLE患者，用GC治疗24周，采用系统性红斑狼疮活动指数（SLEDAI）评定GC治疗SLE疗效，借助HapMap数据库和Haploview软件筛选出中国人群GR基因和HSP90基因标签SNPs，用SNaPshot技术进行基因分型，探讨了HSP90家族基因变异及其与GR基因交互效应对GC治疗SLE疗效的预测作用。本课题取得了如下研究结果：（1）发现GR基因上的多个SNPs可能影响GC治疗SLE患者生活质量的改善；（2）发现HSP90AA1基因上的SNPs rs7160651，rs10873531和rs2298877可预测GC治疗SLE的疗效；（3）发现HSP90AA2基因上的SNP rs6484340可能影响GC治疗SLE患者生活质量的改善；（4）发现HSP90AB1上的SNP rs9367190可能影响GC治疗SLE的疗效；（5）发现HSP90B1上的SNP rs12426382可预测GC治疗SLE的疗效，多个SNPs可能影响GC治疗SLE患者生活质量的改善；（6）发现TRAP1基因上的SNPs rs4786428，rs3751842，rs3794701，rs12597773，rs6500550，rs17183750和rs6500552可能影响GC治疗SLE的疗效，多个SNPs可能影响GC治疗SLE患者生活质量的改善；（7）发现HSP90基因和GR基因在GC治疗SLE患者疗效中存在交互效应；（8）未发现HSP90基因和环境因素在GC治疗SLE患者的疗效中的存在交互效应；（9）发现多个HSP90基因单倍型和GC治疗SLE患者疗效之间存在关联。这些结果为指导SLE患者个体化治疗，改善SLE患者预后，提高其生活质量提供了理论依据，并为下一步开发GC治疗SLE疗效预测基因试剂盒打下了基础。