mtDNA遗传变异及其与核编码线粒体蛋白基因TRAP1遗传变异的互作在SLE发生、治疗疗效预测及预后判断中作用

In recent years, increasingly importance has been attached to the role of genetic variations within mitochondrial DNA (mtDNA) in systemic lupus erythematosus (SLE). But further studies based on multi-stage and larger sample size design are still needed. Many studies have shown that interaction between mtDNA and nuclear DNA (nDNA) paly an important role in the occurrence and development of many diseases. But there is a lack of such research in SLE. Our research group has discovered that genetic variations within nuclear gene TRAP1 coding for mitochondrial protein play an important role in the occurrence of SLE and the efficacy of glucocorticoids in patients with SLE. Our pre-experimental results suggested that genetic variations within mtDNA may play a role in the occurrence of SLE and the variability of efficacy of glucocorticoids in patients with SLE, and there may be interaction effect between mtDNA and TRAP1 gene. Based on the aboved evidences, we hypothesized that mtDNA variations and its interaction with nuclear gene TRAP1 may play an important role in the occurrence, development and treatment of SLE. Therefore, the present study will enroll 1000 SLE patients and 1000 normal controls by two-stage design method. Genetic variations will be measured by using next generation sequencing (SNV/InDel), SNaPshot (SNP) and Q-PCR/AccuCopyTM (CNV) technologies. The purpose of the present study is to explore the role of genetic variations within mtDNA and its interaction with nuclear gene TRAP1 in the occurrence, treatment and prognosis of Chinese SLE patients by using case-control, prospective study and functional experiment design methods. The results of the resent study will provide a theoretical basis for guiding the diagnosis, individual medication and prognosis of SLE, and lay a good foundation for the development of the SLE diagnosis, therapeutic effect and prognosis prediction gene kit

mtDNA变异在SLE发生发展中作用近年逐渐受到重视，但缺乏多阶段大样本全面研究；大量研究显示mtDNA与nDNA在许多疾病中存在互作，但SLE中缺此类研究；课题组前期发现核编码线粒体蛋白基因TRAP1变异在SLE发生及激素治疗SLE疗效预测中起重要作用；预实验提示mtDNA变异及其与TRAP1基因变异交互作用可能在SLE发生和疗效预测中起作用。基于此，我们推测mtDNA变异及其与核编码线粒体蛋白基因TRAP1变异互作可能在SLE发生发展及治疗疗效预测中起重要作用。因此，本研究拟采用两阶段法（1000SLE患者和1000对照），联合使用二代测序、SNaPshot和Q-PCR/AccuCopyTM检测技术，运用病例对照研究、前瞻性研究及功能性实验方法全面阐明中国人群中mtDNA变异及其与TRAP1基因变异的互作在SLE发生、治疗疗效预测及预后判断中作用。从而为开发SLE预测基因试剂盒打下基础

当前线粒体基因组（mtDNA）遗传变异在系统性红斑狼疮（SLE）中的作用尚没有得到全面的研究，且缺乏流行病学研究探讨mtDNA遗传变异与SLE患者糖皮质激素（GCs）治疗疗效和预后之间的关联；证据已经显示mtDNA与核基因组（nDNA）在许多疾病的发生发展中存在互作，肿瘤坏死因子受体相关蛋白 1（TRAP1）在线粒体中广泛表达，影响线粒体功能，TRAP1基因属于核编码线粒体蛋白基因，和mtDNA可能存在互作，但在SLE患者中还未见此类报道。本课题收集了1000例SLE患者和1000例正常对照，采用两阶段设计法，联合使用二代测序（SNV/InDel）、SNaPshot分型（SNP）和Q-PCR/AccuCopyTM检测（CNV）技术，运用病例对照研究、前瞻性研究及功能性实验方法探讨了中国人群中mtDNA遗传变异（SNV/InDel/CNV）及其与TRAP1基因变异的互作在SLE发生、治疗疗效预测及预后判断中作用。本课题取得了如下研究结果：（1）发现mtDNA遗传变异（SNV/InDel/CNV）在SLE发生、治疗疗效预测及预后判断中起着重要作用；（2）未发现核编码线粒体蛋白基因TRAP1遗传变异（SNP/CNV）和SLE预后之间存在关联；（3）发现mtDNA遗传变异（SNV/InDel/CNV）和核编码线粒体蛋白基因TRAP1遗传变异（SNP）及环境因素在SLE发生、治疗疗效预测和预后判断中存在交互作用；（4）发现SLE患者阳性mtDNA遗传变异所在区域部分基因和核编码线粒体蛋白基因TRAP1的表达之间存在相关性；（5）发现阳性mtDNA遗传变异和核编码线粒体蛋白基因TRAP1遗传变异存在一定功能。本研究结果有助于今后基于mtDNA遗传变异指导SLE诊断以及预测SLE患者GCs治疗效果和复发风险，对从mtDNA遗传角度了解SLE发生发展及治疗疗效的个体化差异具有重要意义，并为开发SLE诊断及疗效和预后预测基因试剂盒打下了基础。

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