APOE基因型及启动子区多态性与SAH后血管痉挛和再出血的相关性研究
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摘要
目的探讨载脂蛋白E基因(APOE)及启动子区多态性与自发性蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)以及再出血的相关性。
方法采用聚合酶链反应限制性片段长度多态性(PCR-RFLP)检测185例自发性SAH患者,测定APOE基因型多态性,对其中101例患者测定APOE启动子区多态性,通过TCD评定SAH患者出血后的CVS情况。分型结果与CVS和再出血等临床资料等分别采用SPSS13.0软件进行χ2检验和Logistic回归分析。
结果
1. APOE与CVS的关系
各等位基因分布符合Hardy—Weinberg定律,研究样本为遗传平衡群体。在185例SAH患者中,32例APOEε4携带者中有21例(占65.7%)发生CVS,153例非ε4携带者中有56例(占36.7%)发生CVS,ε4携带者的CVS发生率明显高于非ε4等位基因携带者(P=0.022);单因素和多因素Logistic回归均提示ε4是CVS的危险因素。
对其中101例SAH患者APOE启动子区多态性分型,-219T等位基因携带者的CVS发生率为(48.3%,42/87),显著高于-219G等位基因携带者的CVS发生率(37.7%,23/61,P=0.044);单因素和多因素Logistic回归分析发现,-219T仍然是发生CVS的危险因素。
统计分析还显示,CT的Fisher分级3-4级也是发生CVS的危险因素(P=0.041)。
2. APOE与再出血的关系
21例患者发生再出血,尽管APOEε2和APOEε4携带者再出血的比例分别高于非APOEε2和非APOEε4携带者,但这种差异都不具有统计学意义(ε2 P=0.648;ε4 P=0.822);APOEε3携带者再出血的比例低于APOEε3非携带者,但这种差异同样不具有统计学意义(ε3 P=0.606)。按APOE启动子区多态性分型的101例患者中有13例发生再出血,其启动子区基因多态性的差异与再出血并无统计学意义(P>0.05),Logistic回归分析也未发现相关性。
结论
(1)APOEε4等位基因、启动子区-219T等位基因和Fisher分级3-4级是SAH患者发生CVS的危险因素。
(2)未发现APOE基因型及启动子多态性与再出血的相关性。
Objective To investigate the influence of the APOE gene and promoters polymorphisms on cerebral vasospasm (CVS) and rebleeding of patients with spontaneous subarachnoid hemorrhage (SAH). Methods One hundred and eighty-five patients with spontaneous SAH were selected in this study. Venous Blood samples and clinical data of the patients were collected. The APOE polymorphisms of all patients were determined by PCR-RFLP, and the promoters’polymorphisms were determined in 101 patients. Associations of APOE genotypes and promoters polymorphisms with cerebral vasospasm and rebleeding after SAH were analysized byχ2 test, Uni- and multivariate logistic regression (SPSS verion 13.0).
Results
1. The relationship between APOE and CVS.
The distributions of APOE and promoters genotypes and alleles matched Hardy-Weinberg Law. In 185 patients, 21 of 32 (65.7%) patients with ApoEε4 allels showed CVS, while only 56 (36.7%) out of 153 patients without APOEε4 showed it. Incidence rate of CVS in ApoEε4 (+) group was significantly higher than that in ApoEε4 (-) (P=0.022). Uni- and multivariate logistic regression analyses demonstrated that ApoEε4 allels was a risk factor of CVS incidence.
In 101 patients whose promoter polymorphisms were determined, 42 of 87 patients (48.3%) with promoter -219T allels showed CVS, while 23 of 61 patients (37.7%) with -219G allels showed CVS. The Incidence of CVS in -219T group was significantly higher than that in -219G group (P=0.044). Uni- and multivariate logistic regression analyses also show that promoter -219T was a risk factor of CVS incidence.
The 3-4 grade of Fisher scale was also a risk factor of CVS (P=0.041).
2. The relationship between APOE and rebleeding.
Though the ratio of rebleeding in either APOEε2 or APOEε24 carriers was higher than that of either non- APOEε2 or non- APOEε4 carriers repectively, no statistical significances were found (ε2 P=0.648,ε4 P=0.822). There was also no statistical difference in percentage of rebleeding between APOEε3 and non- APOEε3 carriers even though less cases of rebleeding were obversed in patients with APOEε3 (P=0.606).There were 13 patients had history of rebleeding in the 101 patients whose promoter polymorphisms were determined.χ2 test and logistic regression analyses showed insignificant differences in association of APOE promoter polymorphisms with rebleeding(P>0.05)
Conclusions
1. Our findings suggested that the patients with APOEε4、-219T promoter alleles and 3-4 grade of Fisher scale predispose to CVS after spontaneous SAH.
2. The relationship of APOE and promoter polymorphisms with rebleeding after SAH is not verified and needs further study.
方法采用聚合酶链反应限制性片段长度多态性(PCR-RFLP)检测185例自发性SAH患者,测定APOE基因型多态性,对其中101例患者测定APOE启动子区多态性,通过TCD评定SAH患者出血后的CVS情况。分型结果与CVS和再出血等临床资料等分别采用SPSS13.0软件进行χ2检验和Logistic回归分析。
结果
1. APOE与CVS的关系
各等位基因分布符合Hardy—Weinberg定律,研究样本为遗传平衡群体。在185例SAH患者中,32例APOEε4携带者中有21例(占65.7%)发生CVS,153例非ε4携带者中有56例(占36.7%)发生CVS,ε4携带者的CVS发生率明显高于非ε4等位基因携带者(P=0.022);单因素和多因素Logistic回归均提示ε4是CVS的危险因素。
对其中101例SAH患者APOE启动子区多态性分型,-219T等位基因携带者的CVS发生率为(48.3%,42/87),显著高于-219G等位基因携带者的CVS发生率(37.7%,23/61,P=0.044);单因素和多因素Logistic回归分析发现,-219T仍然是发生CVS的危险因素。
统计分析还显示,CT的Fisher分级3-4级也是发生CVS的危险因素(P=0.041)。
2. APOE与再出血的关系
21例患者发生再出血,尽管APOEε2和APOEε4携带者再出血的比例分别高于非APOEε2和非APOEε4携带者,但这种差异都不具有统计学意义(ε2 P=0.648;ε4 P=0.822);APOEε3携带者再出血的比例低于APOEε3非携带者,但这种差异同样不具有统计学意义(ε3 P=0.606)。按APOE启动子区多态性分型的101例患者中有13例发生再出血,其启动子区基因多态性的差异与再出血并无统计学意义(P>0.05),Logistic回归分析也未发现相关性。
结论
(1)APOEε4等位基因、启动子区-219T等位基因和Fisher分级3-4级是SAH患者发生CVS的危险因素。
(2)未发现APOE基因型及启动子多态性与再出血的相关性。
Objective To investigate the influence of the APOE gene and promoters polymorphisms on cerebral vasospasm (CVS) and rebleeding of patients with spontaneous subarachnoid hemorrhage (SAH). Methods One hundred and eighty-five patients with spontaneous SAH were selected in this study. Venous Blood samples and clinical data of the patients were collected. The APOE polymorphisms of all patients were determined by PCR-RFLP, and the promoters’polymorphisms were determined in 101 patients. Associations of APOE genotypes and promoters polymorphisms with cerebral vasospasm and rebleeding after SAH were analysized byχ2 test, Uni- and multivariate logistic regression (SPSS verion 13.0).
Results
1. The relationship between APOE and CVS.
The distributions of APOE and promoters genotypes and alleles matched Hardy-Weinberg Law. In 185 patients, 21 of 32 (65.7%) patients with ApoEε4 allels showed CVS, while only 56 (36.7%) out of 153 patients without APOEε4 showed it. Incidence rate of CVS in ApoEε4 (+) group was significantly higher than that in ApoEε4 (-) (P=0.022). Uni- and multivariate logistic regression analyses demonstrated that ApoEε4 allels was a risk factor of CVS incidence.
In 101 patients whose promoter polymorphisms were determined, 42 of 87 patients (48.3%) with promoter -219T allels showed CVS, while 23 of 61 patients (37.7%) with -219G allels showed CVS. The Incidence of CVS in -219T group was significantly higher than that in -219G group (P=0.044). Uni- and multivariate logistic regression analyses also show that promoter -219T was a risk factor of CVS incidence.
The 3-4 grade of Fisher scale was also a risk factor of CVS (P=0.041).
2. The relationship between APOE and rebleeding.
Though the ratio of rebleeding in either APOEε2 or APOEε24 carriers was higher than that of either non- APOEε2 or non- APOEε4 carriers repectively, no statistical significances were found (ε2 P=0.648,ε4 P=0.822). There was also no statistical difference in percentage of rebleeding between APOEε3 and non- APOEε3 carriers even though less cases of rebleeding were obversed in patients with APOEε3 (P=0.606).There were 13 patients had history of rebleeding in the 101 patients whose promoter polymorphisms were determined.χ2 test and logistic regression analyses showed insignificant differences in association of APOE promoter polymorphisms with rebleeding(P>0.05)
Conclusions
1. Our findings suggested that the patients with APOEε4、-219T promoter alleles and 3-4 grade of Fisher scale predispose to CVS after spontaneous SAH.
2. The relationship of APOE and promoter polymorphisms with rebleeding after SAH is not verified and needs further study.
引文
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