环氧二十碳三烯酸受EPHX2基因调控与急性缺血性小卒中后早期神经功能恶化发生相关

Epoxyeicosatrienoic acids are related to early neurological deterioration and mediated by EPHX2 gene variants in acute minor ischemic stroke

目的:探究环氧二十碳三烯酸(EETs)与急性缺血性小卒中(MIS)后早期神经功能恶化(END)发生的相关性及其是否受EPHX2基因的调控。方法:本研究为前瞻性观察性研究。连续纳入2013年3月至2015年6月德阳市人民医院、温州医科大学第二附属医院和温州医科大学第三附属医院收治的首次发病且发病在24 h内的急性MIS患者。入院时对所有患者的血浆EETs水平进行检测,并检测其EPHX2基因rs751141单核苷酸多态性。主要终点为患者在入院10 d内出现END(END定义为美国国立卫生研究院卒中量表评分与入院时基线水平相比增加2分及以上者)。结果:共纳入322例患者,其中85例(26.4%)发生了END。与未发生END患者[(68.4±8.1)nmol/L]相比,发生END患者入院时EETs水平[(60.3±7.3)nmol/L]显著降低(t=8.464,P<0.001),EPHX2基因rs751141 GG频率分布明显增高[发生END者66/85(77.6%),未发生END者123/237(51.9%),χ^(2)=17.130,P<0.001]。EPHX2基因rs751141 GG携带者EETs水平较低[GG型:(59.6±7.8)nmol/L;AG型:(67.9±8.2)nmol/L;AA型:(68.8±3.2)nmol/L,F=9.285,P<0.001]。多因素分析结果表明血浆低水平的EETs(≤64.3 nmol/L)为END发生的独立预测因素之一(31.5~51.3 nmol/L组:OR=2.96,95%CI 1.18~8.77,P=0.02;51.4~64.3 nmol/L组:OR=2.46,95%CI 1.06~6.89,P=0.03)。END的发生与患者3个月时预后不良密切相关(OR=1.82,95%CI 1.46~2.35,P=0.02)。结论:END在急性MIS后常见,且与预后不良相关。急性MIS后END与EETs水平降低和EPHX2基因rs751141 GG频率分布明显增高有关。

Objective To investigate the association of plasma epoxyeicosatrienoic acids(EETs)with early neurological deterioration(END),and whether EETs are mediated by EPHX2 gene variants in patients with minor ischemic stroke(MIS).Methods This is a prospective,multi-center observational study in patients with acute MIS in the Chinese population.Acute MIS patients with the first onset and onset within 24 hours who were admitted to Deyang People′s Hospital,the Second Affiliated Hospital of Wenzhou Medical University and the Third Affiliated Hospital of Wenzhou Medical University from March 2013 to June 2015 were recruited.Plasma EETs levels were measured on admission.Single nucleotide polymorphisms of EPHX2 gene rs751141 were genotyped using mass spectrometry.The primary outcome was END within 10 days after admission.END was defined as an increase in National Institutes of Health Stroke Scale score of 2 or more points.Results A total of 322 patients were enrolled,of which 85(26.4%)patients experienced END.EETs levels were significantly lower in patients with END[(60.3±7.3)nmol/L]compared to patients without END[(68.4±8.1)nmol/L,t=8.464,P<0.001].Frequency of EPHX2 gene rs751141 GG was higher in patients with END[66/85(77.6%)]than in patients without END[123/237(51.9%),χ^(²)=17.130,P<0.001],and patients with EPHX2 gene rs751141 GG genotype showed lower EETs levels[GG:(59.6±7.8)nmol/L,AG:(67.9±8.2)nmol/L,AA:(68.8±3.2)nmol/L,F=9.285,P<0.001].Low level(≤64.3 nmol/L)of EETs was an independent predictor of END(31.5-51.3 nmol/L group:OR=2.96,95%CI 1.18-8.77,P=0.02;51.4-64.3 nmol/L group:OR=2.46,95%CI 1.06-6.89,P=0.03)in multivariate analyses.END was associated with a higher risk of poor outcome(modified Rankin Scale scores 3-6)at 3 months(OR=1.82,95%CI 1.46-2.35,P=0.02).Conclusion END is fairly common and associated with poor outcomes in acute MIS.EPHX2 gene variants may mediate EETs levels,and low levels of EETs are related to END in acute MIS.