幽门螺杆菌感染引起缺血性脑卒中发病风险预测的队列研究

Intracranial atherosclerosis（ICAS）is the main pathological basis of the stroke. Helicobacter pylori (Hp) infection can induce the inflammatory and immune responses and promote the development of ICAS. When Hp infects the vascular endothelium, the endogenous ligands of toll-like receptor 4 (TLR4), such as heat shock protein 60 (HSP60), can be produced. HSP60 can bind to TLR4/CDl4 composite, activate the MyD88-NF-κB signaling pathway, promote the secretion of inflammatory factors and accelerate the development of ICAS. The chitin enzymes protein 40 (YKL-40), a novel inflammatory factor, which can affect the cell migration and tissue remodeling and promote the onset of ICAS. Based on the Hp screening population from the existing Jidong study cohort, a dynamic cohort enrolling 4290 participants will be established. By analyzing the data collected from the eight years investigation and follow-ups and the HSP60, TLR4 and YKL-40 tests, we will investigate whether Hp infection induce and aggravate the systemic inflammatory response and the immune response, promote the development of ICAS, affect the stability of plaque, and cause the stroke. Based on the traditional risk factors of stroke, we try to find the new biomarkers of stroke for establishing the disease alerts model. Finally, we hope to provide the scientific evidences for promoting the Hp eradication therapy and personalizing the preventive measures of stroke at individual level.

颅内动脉粥样硬化(ICAS)是引起脑卒中主要病理基础。幽门螺杆菌(Hp)感染触发炎症反应及诱导免疫反应促进ICAS发生发展。Hp感染血管内皮后，产生Toll样受体4(TLR4)内源性配体与TLR4/CD14复合体结合，如热休克蛋白60(HSP60)，激活MyD88-NF-κB信号通路，促进细胞分泌炎症因子，加速ICAS发生发展。炎症因子甲壳质酶蛋白40(YKL-40)可影响细胞迁移和组织重建促进ICAS形成。本研究拟在前期冀东队列筛检Hp人群基础上，建立4290人动态队列。采用历史前瞻性队列研究方法，通过8年调查随访和开展HSP60、TLR4和YKL-40检测，探讨Hp感染后是否通过加重全身炎症、免疫反应诱发或加重ICAS，影响斑块稳定性，从而导致脑卒中的发生。在脑卒中传统危险因素基础上，寻找新的脑卒中生物标记物，建立早期发病预警模型。为开展Hp根除治疗，采取个体化的预防措施提供科学依据。

本研究采用横断面研究探索幽门螺杆菌(Hp)感染、甲壳质酶蛋白40（YKL-40）与颈动脉粥样硬化（CAS）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免疫球蛋白G型N-糖基（IgG N-糖基）组与随访中新发缺血性脑卒中（IS）的关联，筛选可以用于IS发病风险预测的生物标志物。研究发现：（1）Hp感染与CAS之间存在独立于传统危险因素的关联，Hp感染可单独解释约5%的CAS患病风险。（2）Hp感染导致YKL-40水平升高，YKL-40为CAS的危险因素，提示Hp感染引起YKL-40水平升高或为Hp感染与CAS关联的中间环节。（3）血浆IgG特异性N-糖基特征能够反映IS状态，可将其作为IS早期诊断的生物标志物。上述结果验证了Hp感染与炎症标志物和CAS的相关性，证实血浆IgG N-糖基组与IS之间的关联，筛选了与IS发病相关的早期糖基生物标志物，为动脉粥样硬化和IS的病理机制的研究提供了新思路，为开展Hp根除治疗和为采取疾病的个体化预防和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，已发表英文SCI研究论文共计3篇，接收1篇；参加国内外学术交流2次；培养硕士研究生4名。