Lp-PLA2与高血压患者颅内动脉狭窄相关性的前瞻性研究及功能分析

Intracranial arterial stenosis is one of the most important risk factors of ischemic stroke, and is an ideal intermediate phenotype of genetic study on stroke. Lipoprotein-associated phospholipase A2 （Lp-PLA2）is a novelty inflammatory factor. In our previous study, we found that Lp-PLA2 mass was associated with intracranial arterial stenosis in stroke-free hypertensive patients in Chinese population. Therefore, we hypothesize that Lp-PLA2 related genes may associate with intracranial arterial stenosis. To test the hypothesis, we aim to (1) carry out a five years prospective study in 955 asymptomatic hypertension patients, in order to detect the relationship between Lp-PLA2 related genes and intracranial arterial stenosis in stroke free hypertensive patients, (2) explore the effect of blood pressure level and blood pressure variance on association of Lp-PLA2 related genes with intracranial arterial stenosis, (3) test the effect of the positive loci on the Lp-PLA2 expression and enzyme activity in peripheral blood monocyte derived macrophage. This study will illustrate the relationship of Lp-PLA2 and the pathogenesis of intracranial arterial stenosis in stroke-free hypertensive patients in Chinese population, and provide the new evidence for stroke prevention and treatment.

颅内动脉狭窄是中国人群缺血性脑卒中的重要危险因素,也是脑卒中遗传学研究理想的中间表型。脂蛋白相关磷脂酶A2（Lp-PLA2）是近年来广受关注的炎症因子。我们前期在未发生过脑卒中的高血压患者中，发现Lp-PLA2的血浆水平与颅内动脉狭窄相关。因此我们假设，Lp-PLA2相关基因可能与中国人群颅内动脉狭窄的发生相关。为验证以上假说，拟开展以下工作：（1）对955例未发生过脑卒中的高血压患者进行为期5年的随访，研究Lp-PLA2相关位点与高血压患者颅内动脉狭窄发生和发展的关系;（2）研究血压水平及血压的波动对于Lp-PLA2相关基因与高血压患者颅内动脉狭窄相关性的影响;（3）研究发现阳性位点对于外周血单核细胞-诱导巨噬细胞Lp-PLA2浓度和活性的影响。从而阐明Lp-PLA2与我国高血压患者颅内动脉狭窄发生发展的关系，为高血压患者脑卒中个体化预防和治疗提供新的证据。

颅内动脉狭窄是中国人群缺血性脑卒中的重要危险因素，人血浆脂蛋白相关磷脂酶A2（Lp-PLA2）是一种与动脉粥样硬化密切相关的新型炎症标记物。本研究在955例不伴有脑卒中史的高血压患者中，对Lp-PLA2浓度及活性相关的21个基因的42个位点进行基因分型，测定全部样本的Lp-PLA2血浆浓度，并完成对于 955例患者的随访。结果发现ATP2B1-rs1401982与高血压患者颅外动脉斑块和钙化相关；rs17249754、rs3741895与rs2070759颅内血管斑块形成相关；rs7975689与颅外动脉狭窄相关；rs17249754与颅外动脉钙化相关；rs12423192与颅内外动脉钙化相关。PLA2G7-rs7756935与颅内动脉斑块形成有关；rs16874967和rs1805018与颅内动脉狭窄相关；rs1805017和rs1421378与颅外动脉狭窄相关；rs76863441与颅外动脉钙化形成相关。还发现血浆同型半胱氨酸与颅内外动脉狭窄相关，而且该相关性受MTHFR-C677T影响。尿微量白蛋白肌酐比与高血压患者颅内外动脉狭窄密切相关。发现具有和不具有颅内动脉狭窄的高血压患者，其甲基化位点在转录起始点上游5kb到下游5kb之间的甲基化程度有显著差别，两组间有617个CpG位点甲基化|Delta beta|≥0.1，其中28个位点的 |Delta beta|≥0.2。同时进行血浆同型半胱氨酸的EWAS研究，发现了12个p值小于1.07*10-7甲基化位点。