HSP90、HSP70及GR基因遗传变异（SNP/CNV）在SLE发生、治疗疗效预测及预后判断中作用

Our research group have discovered that heat shock protein 90 (HSP90) and glucocorticoid receptor (GR) gene single nucleotide polymorphism (SNP) play an important role in the treatment of systemic lupus erythematosus (SLE). Meanwhile, our pre-experimental results suggested that these SNPs may paly a certain role in the occurrence of SLE. But these findings need to be further explored. Copy number variation (CNV) is another important genetic marker, and the CNVs within HSP90 and GR gene may also be associated with the occurrence and therapeutic effect of glucocorticoid (GC) on SLE. This is a problem deserving of study. There is evidence that heat shock protein 70 (HSP70) is involved in the pathogenesis of SLE. HSP70 and HSP90 are jointly involved in the GC-GR pathway. But there are only a few reports on the association between the genetic variation (SNP/CNV) within HSP70 gene and SLE in Chinese population. Based on the aboved evidence, in the present study, 300 new-onset SLE patients and 300 controls will be enrolled. SLE patients will be treated for 24 weeks, and the therapeutic effect will be evaluated. SNaPshot and AccuCopyTM technologies are used to detect genetic variation (SNP/CNV). The purpose of the present study is to explore the role of genetic variation within HSP90, HSP70 and GR gene in the occurrence and treatment of SLE. The results of the resent study will lay a good foundation for the development of the SLE diagnosis and therapeutic effect prediction gene kit.

课题组前期发现热休克蛋白90（HSP90）和糖皮质激素受体（GR）基因单核苷酸多态性（SNP）在系统性红斑狼疮（SLE）治疗疗效预测中起着重要作用。同时预实验显示这些SNP在SLE发生中也可能起作用，但需进一步证实。拷贝数变异（CNV）是另一个重要遗传标记，HSP90和GR基因上CNV也可能和SLE发生和疗效有关，值得探讨。证据显示热休克蛋白70（HSP70）参与SLE发病，和HSP90共同参与糖皮质激素-GR通路，但中国人群当前少见其遗传变异和SLE关联报道。因此，本研究拟收集300例新发SLE患者和300例对照；对患者治疗24周，评定疗效；用SNaPshot/AccuCopyTM技术检测SNP/CNV；探讨HSP90、HSP70及GR基因遗传变异在SLE发生和治疗疗效预测中作用，本项目完成为开发SLE诊断和疗效预测基因试剂盒打下基础。

证据提示热休克蛋白90（HSP90）、热休克蛋白70（HSP70）及糖皮质激素受体（GR）基因遗传变异可能在SLE发生发展中起一定作用。糖皮质激素（GC）治疗系统性红斑狼疮（SLE）的疗效个体化差异大，药物基因组学研究有望在指导SLE患者合理化用药以及个体化治疗方面实现重大突破。HSP90和HSP70共同参与GC-GR通路，它们的遗传变异可能是GC疗效存在个体化差异的原因之一。本课题收集了300例新发SLE患者和300例正常对照，用GC治疗SLE患者24周，采用系统性红斑狼疮活动指数（SLEDAI）评定了GC治疗SLE患者疗效，采用SNaPshot/AccuCopyTM技术检测了遗传变异（SNP/CNV），探讨了HSP90、HSP70及GR基因遗传变异在SLE发生和治疗疗效预测中的作用。本课题取得了如下研究结果：（1）发现HSP90AA2基因上SNP rs1826330，HSP90AB1基因上SNP rs9367190，HSP90B1基因上SNP rs1165681，TRAP1基因上SNP rs8055172及GR基因上SNPs rs6865292和rs9324921与SLE发病存在关联；（2）发现中国人群HSP90基因及GR基因拷贝数变异（CNV）突变频率较低。TRAP1基因CNV及GR基因CNV和SLE发病有关联，但未发现它们和GC治疗SLE患者疗效有关联；（3）发现中国人群HSP70基因CNV突变频率较低，HSP70基因上SNP rs2075800和SLE发病存在关联，HSPA1L基因CNV和SLE发病存在关联，但未发现它们和GC治疗SLE患者疗效有关联；（4）发现部分HSP90基因、HSP70基因及GR基因遗传变异在SLE的发生及治疗疗效预测的可能存在交互效应；（5）初步功能分析未发现直接的阳性HSP90基因、HSP70基因及GR基因遗传变异（SNP/CNV）功能证据。这些研究结果为指导SLE患者诊断及个体化治疗，提高SLE患者生活质量，改善其预后提供了理论依据，并为下一步开发SLE诊断及疗效预测基因试剂盒打下了基础。

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