缺血性脑中风与E-selectin、ICAM-1及CX3CR1基因多态性的相关性研究

【作者】 张蕴莉；

【导师】 刘学政；

【作者基本信息】 辽宁中医药大学 ， 中西医结合基础， 2008， 博士

【摘要】 目的研究E-选择素(E-selectin)基因第四外显子A561C、趋化因子受体(CXC-chemokine receptor 1,CXCR1)基因T280M及V249I和细胞间黏附分子-1(intercellular adhesion molecule-1,ICAM-1) K469E基因多态性与辽宁汉族人群缺血性脑中风的关系,探讨各基因型与高血压、糖尿病是否是缺血性脑中风的发病危险因素,为揭示缺血性脑中风病因及防治提供依据。方法随机收集2006年11月至2007年2月就诊于辽宁医学院附属一院确诊为缺血性脑中风的患者全血360名及同期体检者全血306名,用聚合酶链反应限制性片段长度多态性(polymerase chain reaction ,PCR restriction fragment length polymorphism, RFLP PCR-RFLP)技术分别检测E-selectin第四外显子A561C基因、ICAM-1 K469E基因和CX3CR1T280M及V249I基因型;采用酶联免疫吸附试验(ELISA)检测缺血性脑中风患者和对照者血清E-选择素水平;采用多因素Logistic回归分析观察各个基因型及等位基因型与缺血性脑中风之间的相互关系。结果1. E-selectin基因第四外显子A561C多态性在两组中的分布差异有统计学意义(X2=6.39,P<0.05),基因型频率的相对风险分析,携带A561C的AC基因型的个体发生缺血性脑中风的风险是AA基因型个体的3.05倍,(OR=3.05,95%CI:1.29-7.20);等位基因频率在两组中也存在着统计学意义(X2 =5.94, P < 0.05,OR = 2.84,95% CI:1.23-6.55),AC基因型携带者的E-selectin血清水平显著高于AA基因[(58.62±14.47)ng/mlVS(45.28±13.86)ng/ml,P<0.01]。Logistic回归分析显示,本研究中高血压、糖尿病、吸烟、A561C多态性、高血脂分别为缺血性脑中风的独立危险因素,P<0.05。2.携带ICAM-1 K469E多态的EE基因型个体明显高于正常对照组(X2=8.03,P<0.01),等位基因E/K在缺血性脑中风组和对照组的差异具有统计学意义(P<0.01)。3.携带CX3CR1 T280M及V249I多态基因个体在缺血性脑中风组和对照组中的差异有显著性,经调整后的OR值分别为0.51(95%CI: 0.27—0.95, P<0.05)和0.48 (95%CI: 0.28—0.83, P<0.05)。I249等位基因频率在两组中也存在着显著性差异,经调整后的OR值为0.54,(95% CI:0.35-0.84, P < 0.05)。V249I等位基因显著减少缺血性脑中风的发病率。结论1.E-selectin基因第四外显子A561C多态性与缺血性脑中风的发病具有相关性, C等位基因可能是辽宁汉族人群缺血性脑中风发病的遗传易感基因。2. ICAM-1 K469E基因多态性与辽宁汉族人群缺血性脑中风的发病也具有相关性,E等位基因可能为辽宁汉族人群缺血性脑中风的一个易感基因,K等位基因则不是易感基因。3. CX3CR1等位基因I249与辽宁汉族人群缺血性脑中风的发病呈负相关。4.高血压、糖尿病、高血脂是独立于三种基因之外的缺血性脑中风发病因素,而吸烟在ICAM-1基因中与ICAM-1 E等位基因、高血压、糖尿病及高血脂因素相互作用引起缺血性脑中风发病,表明吸烟与基因的种类有关。更多还原

【Abstract】 Objective To study the relationship between polymorphisms of E-selectin gene,fractalkine receptor CX3CR1,intercellular adhesion molecule-1(ICAM-1) gene and Cerbral Thrombosis in Han people of Liaoning province and searched the genetic markers of Cerbral Thrombosis.Methods The A561C polymorphism in the exon 4 of E-selectin gene,ICAM-1and CX3CR1 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)analysis and DNA sequencing among 360 patients with Cerbral Thrombosis of Han people in Liaoning and 306 healthy controls.Results 1. There was significant difference in frequencies of allele and genotype in A561C polymorphism between Cerbral Thrombosis and control groups respectively (X2=6.39,P<0.05).The relative risk suffered from Cerbral Thrombosis of AC genotype was 3.05 times of the AA genotype(OR=3.05,95%CI:1.29-7.20). Allele frequency in CC and AC is also significant difference(X2 =5.94 P < 0.05,OR = 2.84,95% CI:1.23-6.55) ,and the serum E-selectin level was significantly higher among carriers of AC genotype as compared with non-carriers (AA genotype) [(58.62±14.47)ng/mlVS(45.28±13.86)ng/ml,P<0.01].2. The EE genotype of ICAM-1 in the cerebral thrombosis group are higher than control group(X2=8.03,P<0.01).The allele gene E/K have statistical significance in two group(X2=11.01,P<0.01).3. There was significant difference in both polymorphisms between patients with Cerbral Thrombosis and controls,the adjusted odds ratio respectively was 0.51(95%CI: 0.27-0.95, P<0.05) and 0.48 (95%CI: 0.28-083, P<0.05). There was significant difference in frequencies of allele I249 between Cerbral Thrombosis and control groups . The adjusted odds ratio was 0.54(95% CI:0.35 -0.84, P < 0.05). CX3CR1 I249 was associated with a markedly reduced risk of Cerbral Thrombosis.Conclusion 1. E-se1ectin A561C polymorphism was associated with Cerbral Thrombosis, and C allele may be a genetic risk factor of Cerbral Thrombosis among Han people,in whom the E-selectin AC genotype carriers maybe increase the risk of Cerbral Thrombosis by enhancing the E-selectin expression.2. ICAM-1E/K polymorphism was associated with Cerbral Thrombosis, and E allele may be a genetic risk factor of Cerbral Thrombosis among Han people,but C allele may have an effect of the protection.3. The results show that CX3CR1 I249 is an independent genetic risk factor for Cerbral Thrombosis and that CX3CR1 may be involved in the pathogenesis of athero sclerotic disease.更多还原