脑微出血影像学分类与血浆血管内皮生长因子水平及载脂蛋白E基因分型的关系研究

目的基于载脂蛋白E(apolipoproteinE,ApoE)基因分型探讨脑微出血(cerebralmicrobleeds,CMBs)影像学分类与血浆血管内皮生长因子(vascular endothelial growth factor,VEGF)水平的关系,为CMBs预警筛查提供有效的生物标志物。方法选择2014年8月-2017年8月在青岛大学附属医院黄岛分院及青岛大学附属威海市中心医院住院治疗的急性脑梗死患者,根据是否存在CMBs分为CMBs组和非CMBs组。对所有脑梗死患者的性别、年龄、简易精神状态评估量表(mini-mentalstateexamination,MMSE)评分、NIHSS评分、高血压病、收缩压、糖尿病、降压药物、抗凝及抗血小板药物使用等因素进行记录。根据CMBs的分布位置不同,参照CMBs解剖评定量表将CMBs分为深部CMBs、脑叶CMBs、幕下CMBs、混合型CMBs。为方便研究,本研究将幕下CMBs归类于深部CMBs。为避免混合型CMBs对研究的干扰,予以剔除。采用ApoE基因分型试剂盒对各组患者进行ApoE基因分型。采用人VEGFQuantikineELISA试剂盒检测血浆VEGF浓度。校正混杂因素使用Logistic分析VEGF与总体CMBs及CMBs不同影像学类型的关系。结果经筛查发现CMBs99例,包括被排除的7例混合型分布(脑叶+深部或脑叶+幕下)的CMBs患者。CMBs组血浆VEGF水平高于非CMBs组(P=0.005)。脑深部CMBs组血浆VEGF水平高于非CMBs组(P=0.009)。高水平的血浆VEGF是CMBs的危险因素(OR 1.59,95%CI 1.02～2.47,P=0.005)。在脑深部CMBs患者中,血浆VEGF水平与ApoE基因型存在交互作用(P=0.01)。在携带ApoEε3/ε3患者中,血浆VEGF水平每增加一个标准差对于脑深部CMBs的多因素校正OR值是0.90(95%CI 0.49～1.20,P=0.73);在ApoEε2或ε4患者中,每增加一个标准差对脑深部CMBs多因素校正OR值是2.83(95%CI1.31～6.10,P=0.008)。结论脑深部CMBs与高水平血浆VEGF有关。血浆VEGF与CMBs的风险联系可能存在ApoE基因型依赖。

Relationship of Imaging Classification of Cerebral Microbleeds and Plasma Vascular Endothelial Growth Factor Level and Apolipoprotein E Phenotype

Objective To investigate the relationship between the imaging classification of cerebral microbleeds
(CMBs) and plasma vascular endothelial growth factor (VEGF) levels based on apolipoprotein E
(ApoE) phenotype, to provide valuable biomarkers for the early warning screening of CMBs.
Methods Patients with acute cerebral infarction who were admitted to the Huangdao Branch of the
Affiliated Hospital of Qingdao University and Weihai Central Hospital of Qingdao University from
August 2014 to August 2017 were selected. All the patients were divided into CMBs and non-CMBs
according to the presence or absence of CMBs. The baseline data included gender, age, mini-mentalstate examination (MMSE) score, NIHSS score, hypertension, systolic blood pressure, diabetes,
antihypertensive drugs, anticoagulation and antiplatelet agents and etc. With reference to the CMBs
Anatomical Rating Scale, the CMBs were divided into deep CMBs, lobe CMBs, subtentorial CMBs,
and mixed CMBs according to the distribution of CMBs. To facilitate the analysis, subtentorial
CMBs were classified as deep CMBs and mixed CMBs were excluded. ApoE genotyping of all
patients were measured using the ApoE genotyping Kit. Plasma VEGF level was measured by
ELISA. After adjusting for the potential confounding factors, logistic regression analysis was used
to analyze the relationship of plasma VEGF level and different imaging classification of CMBs.
Results Ninety nine cases of CMBs were identified, including 7 cases with mixed CMBs who were
excluded. Plasma VEGF levels in CMBs group was significantly higher than that in non-CMBs
group (P =0.05). The plasma VEGF level in deep CMBs group was significantly higher than that
in non-CMBs group (P =0.009). High level of plasma VEGF was a risk factor for CMBs (OR 1.59,
95%CI 1.02-2.47; P =0.05). In patients with deep CMBs, there was an interaction between plasma
VEGF levels and ApoE genotype (P =0.01). In patients with ApoE ε3 /ε3 , the adjusted OR of deep
CMBs for each standard deviation (SD) increase in plasma VEGF levels was 0.90 (95%CI 0.49-
1.20; P =0.73); in patients with ApoE ε2 or ε4 , the adjusted OR of deep CMBs for each SD increase
in plasma VEGF level was 2.83 (95%CI 1.31-6.10; P =0.008).
Conclusions Deep CMBs are associated with the high level of plasma VEGF. The relation of
plasma VEGF with CMBs may have ApoE genotype dependence.