我国五个民族人群原发性高血压与血浆IgG N-糖基组的关联研究

The discovery of ethnic group-specific biomarkers enlightening the prevention and treatment of essential hypertension (EH) will help to curb the sustained rising prevalence rate of EH in the different ethnic groups of China. Inflammatory mechanism of essential hypertension suggests that N-glycosylation alterations of immunoglobulin G (IgG) can cause EH through the inflammatory and anti-inflammatory signaling pathways, thereby we speculated that the alterations of N-glycosylation of IgG in human plasma are early events of hypertension and can be used as a potential warning biomarkers for the disease. The applicant’s former research results showed that the ethnic groups (i.e. Uyghur, Kazakh, Tajik, Kirgiz and Han) in our country could be suitable for exploring potential variances of genetic predisposition to diseases and of efficacy of drug treatments. Based on the sampling spots for the five ethnic groups established by our former project and the N-glycans profiling experimental platforms, which thereby has laid a good foundation for the proposed study, we plan to perform the study of plasma N-glycome of IgG in the five ethnic groups with higher prevalence rate of essential hypertension (EH) by a novel HPLC-based high-throughput N-glycans profiling methods. Based on the glycan profiling of the five ethnic groups in China, this study will be the first attempt to analyze the association of the structures and the levels of plasma N-glycans of IgG with EH, after adjusted for the EH related environmental and genetic factors. We aim to identify the common and specific characterized profilings of the plasma N-glycans of IgG between EH groups and normal controls among the five Chinese ethnic groups, which will benefit for further understanding the pathological mechanism of EH, accumulating epidemiological data of IgG N-glycomes of both the normal controls and EH patients among the different ethnic groups, and providing a theoretical basis for the discovery of new potential targets for drug development and carrying out individual treatment of EH.

发现对防治原发性高血压有启迪意义的人群特异性的生物标志物有助于遏制我国不同民族人群患病率的持续上升。原发性高血压发生的炎症机制提示IgG N-糖基化修饰可通过其对炎症和抗炎信号通路的作用而引发该病，推测IgG N-糖基化改变是高血压发生的早期事件，可作为警示该病发生的潜在标志物。申请人前期研究表明我国新疆少数民族隔离人群和汉族人群是探究慢性病遗传易感性与疗效异质性的适宜人群。本项目拟利用前期建立的上述人群调研现场及HPLC糖基组检测实验平台，探究各民族人群正常对照与其各级高血压患者的血浆IgG N-糖基组基本特征及其校正遗传与环境混杂因素后的变异谱（各人群共同的和特异的糖基组谱型），以寻找人群特异性的高血压早期预警的糖基分子标志物，积累不同人群正常与患者的IgG N-糖基组的流行病学基础研究数据，为深入理解人群特异性的病理机制，发现药物开发潜在的新靶点，开展高血压的个体化诊疗提供科学依据。

发现对防治原发性高血压有启迪意义的人群特异性的生物标志物有助于遏制我国不同民族人群患病率的持续上升。本研究采用高通量糖基组检测技术（高效液相色谱（UPLC）、液相色谱-电喷雾质谱（LC-MS/MS））检测了汉族及四个新疆少数民族人群的血浆IgG N-糖基组特征。分析新疆少数民族人群原发性高血压、2型糖尿病与血浆IgG N-糖基组的关联，探究新疆少数民族人群与汉族人群中正常对照者及原发性高血压患者糖基谱型特征，首次发现：（1）血浆IgG亚型特异性糖基组谱型与血压状态之间关联性具统计学意义，表明可将其作为指示高血压炎性病理过程的早期预警分子生物标志物和治疗新靶点；（2）汉族与新疆各少数民族的高血压状态人群及正常人群间存在共性糖基谱型；（3）新疆各少数民族高血压状态人群具有特异性糖基谱型；（4）血浆IgG N-糖基组通过调节机体的抗炎-促炎状态影响高血压-糖尿病共患病的发生或进展过程，其特征对高血压-糖尿病共患病状态具有良好的预测能力；（5）血浆IgG N-糖基与汉族人群心血管代谢性疾病的危险因素相关；（6）血浆IgG亚型特异性N-糖基特征能够准确地反映2型糖尿病状态，可将其作为2型糖尿病早期诊断的生物标志物；（7）蛋白质糖基化修饰相关的功能基因位点的遗传变异与维族人群的2型糖尿病的发病风险有关联。上述结果证实了血浆IgG N-糖基组与高血压、糖尿病之间的关联，不同人群的血浆IgG N-糖基组特征存在差异性，为原发性高血压、糖尿病的病理机制的研究提供了新思路，为未来开展疾病的个体化诊疗提供了科学依据。