缺血性脑卒中发病风险分层的血浆免疫球蛋白G糖基组生物标志物筛选

Ischemic stroke (IS) is one of the major public health challenges, and will worsen with the increasing incidence of hypertension, hyperglycaemia and hyperlipoidemia; therefore early prediction is of important significance for the prevention of IS. Based on 1) the recognized inflammatory mechanism of IS, 2) N-glycan of immunoglobulin G (IgG) regulates the inflammatory pathways, 3) our findings that the plasma IgG N-glycan associated with hypertension, hyperglycaemia and hyperlipoidemia (the first, ninth and second risk factors of ischemic stroke, and 4) our findings that inflammatory biomarkers Lp-PLA2 associate with cerebral artery atherosclerotic stenosis (CAS) and contribute to the incidence of IS, we hypothesized that abnormal IgG N-glycosylation is the early events of IS, which associate with CAS and function in inflammatory pathways, and finally lead to the occurrence of IS. In this community based prospective cohort, we will investigate the association between IgG N-glycome and CAS or inflammatory biomarkers based on a cross-sectional study, and investigate the association between baseline IgG N-glycome and incidence of IS based on a nested case-control study. We firstly attempt to determine the relation between IgG glycosylation and inflammation state at the population level, and firstly try to screen the IgG glycome biomarkers for risk stratification of ischemic stroke. The study may find novel glycans biomarkers for ischemic stroke, and provide predicated model for screening of high-risk population of ischemic stroke.

缺血性脑卒中(IS)是我国主要疾病负担之一，尽管被广泛研究但仍然缺乏有效的预警标志物。项目组发现免疫球蛋白G(IgG) N-糖基化异常与IS的主要危险因素（高血压、高脂血症及糖尿病）关联，而IgG通过糖基修饰调控炎症且炎症是动脉粥样硬化性狭窄和IS的主要机制；因此假设“IgG N-糖基化异常是IS发病的早期事件(正常或无症状脑动脉狭窄阶段)，其通过调控炎症信号通路，影响IS的发生”。本研究拟采用横断面研究调查血浆IgG N-糖基组与脑动脉狭窄(CAS)或炎症标志物的关联；在前瞻性人群队列中采用巢式病例对照方法探索基线IgG N-糖基组与随访中首发IS的关联，筛选可以用于IS发病风险分层的糖基生物标志物，建立包含传统危险因素、炎症和糖基标志物的IS发病预警模型。本研究首次在人群水平上探讨IgG糖基与炎症状态、CAS及IS发病的关联，将为IS高危人群筛选提供方法并可能发现IS干预性预防的靶点。

本研究采用高通量糖基组检测技术在横断面研究中探索血浆IgG N-糖基化水平与炎症标志物、脑动脉狭窄和缺血性脑卒中的关联，并在前瞻性人群队列中采用巢式病例对照方法研究IgG N-糖基组与随访中新发缺血性脑卒中的关联，筛选可以用于缺血性脑卒中发病风险的生物标志物。首次发现：（1）IgG半乳糖基和唾液酸糖基的缺失以及二等分N-乙酰葡萄胺糖基的增加可能涉及机体炎症的分子机制，可能与缺血性脑卒中的长期慢性炎症状态有关。（2）异常的IgG N-糖基化导致机体抗炎-促炎失平衡而参与脑动脉狭窄、缺血性脑卒中的发病机制。（3）血浆IgG特异性N-糖基特征能够反映缺血性脑卒中状态，可将其作为缺血性脑卒中早期诊断的生物标志物。上述结果验证了血浆IgG N-糖基组与炎症标志物和血脂异常的相关性，证实血浆IgG N-糖基组与脑动脉狭窄、缺血性脑卒中之间的关联，筛选了与缺血性脑卒中发病相关的早期糖基生物标志物，为缺血性脑卒中的病理机制的研究提供了新思路，为开展疾病的个体化诊疗提供了科学依据。本项目按原定计划开展了研究，取得了预期的研究成果，已发表研究论文共计10篇，其中英文SCI收录论文9篇，中文核心期刊论文1篇；参加国内外学术交流3次；培养硕士研究生3名。