CYP4F2、CYP4A11及LTC4S基因多态与缺血性脑卒中相关性研究
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摘要
CYP4F2、CYP4A11及LTC4S基因多态与缺血性脑卒中相关性研究
目的
脑卒中是严重危害人类健康的常见病、多发病,是人类三大死亡原因之一研究已经证实,高血压、糖尿病、血脂异常、吸烟、饮酒、肥胖等一些传统危险因素与脑卒中的发生有关。此外,遗传学研究表明脑卒中的发生有其遗传易感性。脑卒中是遗传和环境因素共同作用的结果,遗传因素在脑卒中的发病中起着重要作用,因此,寻找脑卒中的易感基因,从分子水平认识其发病机制,从而提高对该病的预防,诊断及治疗。
花生四烯酸(arachidonic acid, AA)是人体内最为丰富的物质之一,是人体内多种重要心血管活性物质的前体。CYF4F2 (cytochrome P450, family 4, subfamilyF，polypeptide 2)以及CYP4A11(cytochrome P450,family 4,subfamily A,polypeptide 11)是细胞色素P450家族成员之一,它们的主要功能是催化花生四烯酸生成20-羟二十烷四烯酸(20-hydroxyeicosatetraenoic acid,20-HETE), 20-HETE在调节肾、脑、骨骼肌和肠系膜动脉血管平滑肌肌源性收缩中发挥重要作用,此外20-HETE还具有调节血压的作用。近来研究报道,20-HETE能引起出血性脑卒中后血管痉挛,参与缺血性脑卒中的发生发展过程。CYP4F2和CYP4A11是催化花生四烯酸生成20-HETE的主要合成酶。近来证实,CYP4F2基因的一个单核苷酸多态性(single nucleotide polymorphism, SNP) rs2108622会导致花生四烯酸生成20-HETE减少。本研究的目的之一是应用病例对照的方法研究CYP4F2和CYP4A11基因多态与缺血性脑卒中(Ischemic stroke, IS)的关系。
白三烯C4合成酶(leukotriene C4 synthase, LTC4S)是半胱酰白三烯合成通路中一个重要的酶,半胱酰白三烯是很强的炎症介质,广泛参与多种炎症病理过程,半胱氨酰白三烯能通过激活其受体半胱酰白三烯受体1(cysteinyl leukotrienereceptor 1, CysTL1)和半胱酰白三烯受体2 (cysteinyl leukotriene receptor 2, CySTL2),改变内皮细胞通透性以及血管内皮细胞的迁移,介导平滑肌痉挛、微血管渗漏等。近年研究表明白三烯(leukotriene, LTs)与动脉粥样硬化及增加心血管疾病患病率有关。本研究的另一目的就是应用病例对照的方法研究LTC4S基因多态与缺血性脑卒中的关系。
方法
采用病例-对照研究方法,缺血性脑卒中(Ischemic stroke, IS)组选取中国北方IS患者302例,男性193例、女性109例,年龄在40-80岁间,均为汉族,无亲缘关系；选取性别、年龄与IS组相匹配的健康个体350例作为对照组,男性212例、女138例；在此基础上将IS组按病因不同分为大血管组(血栓性脑梗死组)和小血管组(腔隙性脑梗死组)。应用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法检测CYF4F2基因rs2108622、rs3093100、rs3093105、rs3093135位点,CYP4A11基因rs9333025位点和LTC4S基因rs730012位点的多态性,应用基质辅助激光解吸附电离飞行时间质谱法(MALDI-TOF)检测rs3776924、rs1558139位点多态性；基因分型结果经双脱氧末端终止测序法进一步确认。用拟合优度χ2检验验证每个位点SNP基因型在抽样群体中的分布是否符合Hardy-Weinberg平衡。对于单位点的SNP数据,采用SPSS13.0统计软件χ2 Fisher's精确概率法检验其基因型、等位基因型在对照组与IS组及各亚组中的频率分布差异、风险度分析,最后结合临床资料,对相关数据进行条件Logistic回归方法排除传统混杂因素的干扰,以P<0.05为检验水准。用Shesis在线软件计算CYF4F2基因单倍型的频率。用UNPHASED软件分析CYF4F2基因、CYP4A11基因对IS的联合作用。
结果
1、所有研究对象的每个SNP位点的基因型在抽样群体中的分布均符合Hardy-Weinberg平衡(P>0.05),表示所选取的样本具有人群代表性适合做遗传学分析。
2、CYF4F2基因rs2108622位点多态性在IS组与对照组的频率分布：rs2108622位点G／G基因型频率在男性IS组明显高于男性对照组(OR=2.53；95%CI：1.15-5.56；P=0.018),应用Logistic回归分析校正后仍有统计学差异(OR=1.788；95%CI:1.120～2.854; P=0.015 (G/G vs A/A+G/A)), (OR=3.14; 95%CI 1.283～7.71; P=0.012 (GG+GA vs AA)).G等位基因的频率男性IS组明显高于男性对照组(OR=1.48；95%CI：1.09-2.02；P=0.013)。而该位点在病例组与对照组之间以及女性病例组与对照组之间的差异无统计学意义(P>0.05)。
3、CYF4F2基因rs3093100、rs3093105、rs3093135以及rs1558139位点多态性在IS组与对照组的频率分布：rs3093100位点C／C基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；C等位基因的频率各组之间比较也无统计学意义。rs3093105位点T／T基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；T等位基因的频率各组之间比较也无统计学意义。rs3093135位点T／T基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；T等位基因的频率各组之间比较也无统计学意义。rs1558139位点G／G基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；G等位基因的频率各组之间比较也无统计学意义。
4、CYF4F2基因单倍型在对照组与IS组及IS亚组中频率分布：由rs2108622、rs3093100、rs3093105和rs3093135组建单倍型,在IS组与对照组构建5个单倍型,GGGT单倍型在IS组中的分布频率明显高于对照组,携带GGGT单倍型的个体,患缺血性卒中的风险率增加至1.339倍(OR=1.339；95%CI：1.051-1.706；P=0.017)。在男性IS组与男性对照组构建6个单倍体型,GGGT单倍型在IS组中的分布频率明显高于对照组,携带GGGT单倍型的个体,患缺血性卒中的风险率增加至1.545倍(OR=1.545；95%CI：1.144-2.087；P=0.004)。在女性IS组与女性对照组构建8个单倍型,两组间比较无统计学差异。
5、CYP4A11基因rs9333025位点的多态性在IS组与对照组的频率分布：rs9333025位点IS组与对照组比较,G／G基因型的频率高于对照组,而G/A+A/A的频率低于对照组,基因型频率比较χ2=9.311,P=0.02,OR=1.698,95%CI1.207-2.389。应用logistic回归分析校正传统危险因素(高血压、糖尿病、高脂血症、吸烟等)后GG基因型频病例组和对照组比较差异仍然有统计学意义,χ2=6.715,P=0.01,OR=1.721,95%CI：1.141-2.594。
6、LTC4S基因rs730012位点多态性在对照组与IS组中频率分布：IS组与对照组比较C／C基因型的频率明显高于对照组,A／C,A／A基因型的频率均低于对照组,基因频率比较χ2=3.41,P=0.011,OR=3.41,95%CI：1.257-9.245；A与C等位基因频率比较χ2=11.057,df=1,OR=1.680,95%CI=1.235～2.286,P=0.001。应用Logistic回归分析校正后仍有统计学意义(OR=0.881；95%CI：0.786-0.989；P=0.031)。将IS组按不同病因分为大血管组(血栓性脑梗死组)和小血管组(腔隙性脑梗死组)后,大血管组与对照组比较C／C基因型的频率明显低于对照组。
7、LTC4S基因rs331446827位点多态性在对照组与IS组中频率分布：rs331446827位点C／C基因型的频率IS组与对照组比较无统计学意义(P>0.05)。
结论
1、CYP4F2基因rs2108622位点GG基因型可能是中国北方汉族人群男性缺血性卒中的独立的危险因素,G等位基因可以增加男性患缺血性脑卒中的遗传易感性。
2、CYP4F2基因rs3093100、rs3093105、rs3093135以及rs1558139位点的基因多态性与缺血性脑卒中无关。
3、CYP4F2基因的GGGT单倍型可能是IS的风险单倍型。
4、CYP4A11基因rs9333025位点GG基因型与IS具有相关性,G等位基因增加缺血性脑卒中的遗传易感性
5、LTC4S基因rs730012位点C／C基因型可能具有保护作用的基因。
6、LTC4S基因rs3776924位点的多态性与IS无关。
Effect of Polymorphisms of CYP4F2、CYP4A11 and LTC4S Gene on Ischemic Stroke
Objective
Cerebrovascular disease(CVD) is one of the three major causes of death, and is harmful to human health. Ischemic stroke(IS) of incidence of cerebrovascular disease accounted for 80%.IS is a heterogeneous multifactorial disorder. In addition to conventional risk factors such as hypertension, diabetes mellitus, and smoking, evidence from animals and clinical and epidemiological studies have repeatedly supported the likelihood of a genetic contribution to CI susceptibility. Epidemiological data provide substantial evidence for a genetic component to the disorder. Identifying accurately its genetic determinants is a key issue in order to improve diagnosis and treatment strategies and to reduce stroke's huge public health burden.
Arachidonic acid (AA) is the most abundant substances in the human body which is one of the important precursors of cardiovascular active substances. It has been reported that 20-hydroxyeicosatetraenoic acid (HETE) plays an important role in the pathogenesis of ischemic stroke.20-HETE is a metabolite of arachidonic acid (AA) generated by the CYP4F2 and CYP4A11 subfamily of cytochrome P450 (CYP450) and plays a significant role in the regulation of vascular tone in renal, cerebral, coronary, and skeletal muscle arterioles, and in the pulmonary circulation. CYP450 enzymes form the 3rd pathway of arachidonic acid (AA) metabolize AA. CYP450-derived arachidonic acid metabolites play a role in the modulation of cerebrovascular pathology and physiology. CYP4F2 and CYP4A11 are members of the family of CYP450 enzymes, and mainly act as enzymes that is involved not only in the metabolism of leukotriene B4 (LTB4), but also 20-HETE. It has been reported that cerebral infarction is associated with the polymorphism of rs2108622.However the association results of these candidate genes in different regions and for different ethnic population have not been effectively reapeated and confirmed. In view of northern Chinese population with higher incidence of IS, it is necessary to carry out an association study of candidated susceptible genes aimed at northern China region Han population IS.
Atherosclerosis is an important pathophysiological basis of IS, and inflammatory reaction process is of great significance in atherosclerosis formation, Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Studies in animals and in vitro suggest that both LTB4 and cysteinyl leukotrienes participate in the development of atherosclerotic lesions. LTC4 synthase lead LTA4 to LTC4, D4 and E4 (collectively referred to as the cysteinyl-LTs). so our study selected inflammation-related LTC4 synthase gene. By introducing candidate genes case-control association analysis, we mesured LTC4 synthase gene allele frequencies between IS group. So we can provide IS molecular epidemiology data for comprehensively understanding IS potential genetic mechanisms and more early IS molecular biology diagnosis indicators.
Materials and methods
A case-control design was introduced. The subjects of IS group were consecutively recruited from northern China region patients with a total of 302 cases male 193,female 109, aged 40-80 years old, Han nationality, no consanguinity with each other. The controls matched by age, sex, and ethnic orign were recruited from the same patients geographic region, with a total of 350 cases, male 212, female 138. Accordting to the different causes the patients were divided into two subgroups:the large vessels group (thrombotic cerebral infarction group) and the small vessels group(lacunar infarction group). CYP4F2 gene rs2108622, rs3093100, rs3093105, rs3093135; CYP4A11 gene rs9333025 and LTC4S gene rs73002 SNPs were genotyped by polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP) analysis.CYP4F2 gene rs1558139 and LTC4S gene rs331446829 SNPs were genotyped by means of Matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF) primer extension reaction. Genotyping results were confirmed by squencing method. SPSS 13.0 statistical software was used for data processing. Continuous variables were expressed as mean±SE and were assessed by One-Way ANOVA. Genotype and allele frequencies were calculated for control group and each of the patient groups. Univariate comparisons of allele and genotype distributions were done usingχ2 test. Theχ2 goodness of fit test was used to test for deviation of genotype distribution from Hardy-Weinberg equilibrium. Conditional Logistic Regression adjusted for IS traditional risk factors including age, blood pressure, blood sugar, blood lipids and smoking. The influence of CYP4F2、CYP4A11 and LTC4S gene polymorphisms on IS was indicated by odds ratio(OR) and 95% confidenc(CI) with P＜0.05 as significant criteria. Haplotype-based analysis was infered by using Shesis online-software. The synergistic action of CYP4F2 gene、CYP4Allgene and LTC4S gene for IS was analysed by UNPHASED 3.0.7 version software.
Results
1. The genotype frequencies of all SNPs conformed to the expectations of Hardy-Weinberg equilibrium(P＞0.05). It was suggested that the selected samples could represent the population and were suitable for genetic analysis.
2. CYP4F2 gene rs2108622 SNP frequencies distributions among the patients and the controls:rs2108622 G/G genotyp frequencies of the male IS group were higher than the male control group (OR=2.53; 95%CI:1.15-5.56; P=0.018), and after logistic regression the differece was still significant OR=1.78; 95%CI:1.120～2.854; P=0.015 (GG vs AA+GA)), (OR=3.14; 95%CI 1.283-7.71; P=0.012(GG+GA vs AA)). G allele frequencies of the male IS group were higher than the male control group (OR=1.48; 95%CI:1.09-2.02; P=0.013).There were no significant differences with regard to G/G genotyp frequencies between the IS patients and the control and female.
3. CYP4F2 gene rs3093100、rs3093105、rs3093135 and rs1558139 SNPs frequencies distributions among the patients and the controls:There were no significant differences with regard to rs3093100 C/C genotyp frequencies between the IS patients and the control,males and females (P＞0.05). There were no significant differences with regard to rs3093105 T/T genotyp frequencies between the IS patients and the control,males and females (P＞0.05). There were no significant differences with regard to rs3093135 T/T genotyp frequencies between the IS patients and the control,males and females (P＞0.05). There were no significant differences with regard to rs1558139 G/G genotyp frequencies between the IS patients and the control,males and females (P＞0.05).
4. CYP4F2 gene haplotype frequencies among the patients and the controls:5 haplotypes were identified among the patients and the controls, GGGT haplotype frequencies of the IS group were higher than the control group (OR= 1.339; 95%CI: 1.051-1.706; P=0.017);6 haplotypes were identified among the male patients and the male controls, the GGGT haplotype frequencies of the male cases were higher than the male control group (OR= 1.545; 95%CI:1.144-2.087; P=0.004); 8 haplotypes were identified among the female patients and the female, significant differences of all the haplotypes were not observed in the female IS group and the female control group (P＜0.05).
5. CYP4A11 gene rs9333025 SNP frequencies distributions among the patients and the controls:rs9333025G/G genotyp frequencies of IS group were higher than the control group(P=0.02, OR=1.698,95%CI:1.207-2.389), and after logistic regression the differece was still significant(P=0.01,OR=1.721,95%CI:1.141-2.594)rs9333025 G allele frequencies of the IS group were higher than the control group (OR=1.661; 95%CI:1.22-2.24; P=0.001)
6. LTC4S gene rs730012 SNP frequencies distributions among the patients and the controls:rs730012 C/C genotyp frequencies of the control group were lower than the IS group (OR=3.41; 95%CI:1.257-9.245;P=0.011), and after logistic regression the differece was still significant (OR=0.892; 95%CI:0.797-0.998; P=0.047)
7. LTC4S gene rs331446827 SNP frequencies distributions among the patients and the controls:There were no significant differences with regard to rs331446827 A/A genotyp frequencies between the IS patients and the control. Conclusions
1、CYP4F2 gene rs2108622 G/G genotype might be the independent risk factors of northern China region han population ischemic strke, and its risk mainly came from G allele.
2、There were no association between the polymorphisms of rs3093100、 rs3093105、rs3093135 and rsl558139 and northern China region han population ischemic strke.
3、CYP4F2 gene GCGA haplotype might be at-risk haplotype of IS
4、CYP4A11 gene rs9333025 G/G genotype might be associated with IS.G allele might be risk allele
5、LTC4S gene rs730012 C/C genotype might be protective.
6、There was no association between the SNP of rs331446827 and IS.
目的
脑卒中是严重危害人类健康的常见病、多发病,是人类三大死亡原因之一研究已经证实,高血压、糖尿病、血脂异常、吸烟、饮酒、肥胖等一些传统危险因素与脑卒中的发生有关。此外,遗传学研究表明脑卒中的发生有其遗传易感性。脑卒中是遗传和环境因素共同作用的结果,遗传因素在脑卒中的发病中起着重要作用,因此,寻找脑卒中的易感基因,从分子水平认识其发病机制,从而提高对该病的预防,诊断及治疗。
花生四烯酸(arachidonic acid, AA)是人体内最为丰富的物质之一,是人体内多种重要心血管活性物质的前体。CYF4F2 (cytochrome P450, family 4, subfamilyF，polypeptide 2)以及CYP4A11(cytochrome P450,family 4,subfamily A,polypeptide 11)是细胞色素P450家族成员之一,它们的主要功能是催化花生四烯酸生成20-羟二十烷四烯酸(20-hydroxyeicosatetraenoic acid,20-HETE), 20-HETE在调节肾、脑、骨骼肌和肠系膜动脉血管平滑肌肌源性收缩中发挥重要作用,此外20-HETE还具有调节血压的作用。近来研究报道,20-HETE能引起出血性脑卒中后血管痉挛,参与缺血性脑卒中的发生发展过程。CYP4F2和CYP4A11是催化花生四烯酸生成20-HETE的主要合成酶。近来证实,CYP4F2基因的一个单核苷酸多态性(single nucleotide polymorphism, SNP) rs2108622会导致花生四烯酸生成20-HETE减少。本研究的目的之一是应用病例对照的方法研究CYP4F2和CYP4A11基因多态与缺血性脑卒中(Ischemic stroke, IS)的关系。
白三烯C4合成酶(leukotriene C4 synthase, LTC4S)是半胱酰白三烯合成通路中一个重要的酶,半胱酰白三烯是很强的炎症介质,广泛参与多种炎症病理过程,半胱氨酰白三烯能通过激活其受体半胱酰白三烯受体1(cysteinyl leukotrienereceptor 1, CysTL1)和半胱酰白三烯受体2 (cysteinyl leukotriene receptor 2, CySTL2),改变内皮细胞通透性以及血管内皮细胞的迁移,介导平滑肌痉挛、微血管渗漏等。近年研究表明白三烯(leukotriene, LTs)与动脉粥样硬化及增加心血管疾病患病率有关。本研究的另一目的就是应用病例对照的方法研究LTC4S基因多态与缺血性脑卒中的关系。
方法
采用病例-对照研究方法,缺血性脑卒中(Ischemic stroke, IS)组选取中国北方IS患者302例,男性193例、女性109例,年龄在40-80岁间,均为汉族,无亲缘关系；选取性别、年龄与IS组相匹配的健康个体350例作为对照组,男性212例、女138例；在此基础上将IS组按病因不同分为大血管组(血栓性脑梗死组)和小血管组(腔隙性脑梗死组)。应用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法检测CYF4F2基因rs2108622、rs3093100、rs3093105、rs3093135位点,CYP4A11基因rs9333025位点和LTC4S基因rs730012位点的多态性,应用基质辅助激光解吸附电离飞行时间质谱法(MALDI-TOF)检测rs3776924、rs1558139位点多态性；基因分型结果经双脱氧末端终止测序法进一步确认。用拟合优度χ2检验验证每个位点SNP基因型在抽样群体中的分布是否符合Hardy-Weinberg平衡。对于单位点的SNP数据,采用SPSS13.0统计软件χ2 Fisher's精确概率法检验其基因型、等位基因型在对照组与IS组及各亚组中的频率分布差异、风险度分析,最后结合临床资料,对相关数据进行条件Logistic回归方法排除传统混杂因素的干扰,以P<0.05为检验水准。用Shesis在线软件计算CYF4F2基因单倍型的频率。用UNPHASED软件分析CYF4F2基因、CYP4A11基因对IS的联合作用。
结果
1、所有研究对象的每个SNP位点的基因型在抽样群体中的分布均符合Hardy-Weinberg平衡(P>0.05),表示所选取的样本具有人群代表性适合做遗传学分析。
2、CYF4F2基因rs2108622位点多态性在IS组与对照组的频率分布：rs2108622位点G／G基因型频率在男性IS组明显高于男性对照组(OR=2.53；95%CI：1.15-5.56；P=0.018),应用Logistic回归分析校正后仍有统计学差异(OR=1.788；95%CI:1.120～2.854; P=0.015 (G/G vs A/A+G/A)), (OR=3.14; 95%CI 1.283～7.71; P=0.012 (GG+GA vs AA)).G等位基因的频率男性IS组明显高于男性对照组(OR=1.48；95%CI：1.09-2.02；P=0.013)。而该位点在病例组与对照组之间以及女性病例组与对照组之间的差异无统计学意义(P>0.05)。
3、CYF4F2基因rs3093100、rs3093105、rs3093135以及rs1558139位点多态性在IS组与对照组的频率分布：rs3093100位点C／C基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；C等位基因的频率各组之间比较也无统计学意义。rs3093105位点T／T基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；T等位基因的频率各组之间比较也无统计学意义。rs3093135位点T／T基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；T等位基因的频率各组之间比较也无统计学意义。rs1558139位点G／G基因型的频率IS组与对照组比较、男性IS组与男性对照组比较以及女性IS组与女性对照组比较均无统计学意义(P>0.05)；G等位基因的频率各组之间比较也无统计学意义。
4、CYF4F2基因单倍型在对照组与IS组及IS亚组中频率分布：由rs2108622、rs3093100、rs3093105和rs3093135组建单倍型,在IS组与对照组构建5个单倍型,GGGT单倍型在IS组中的分布频率明显高于对照组,携带GGGT单倍型的个体,患缺血性卒中的风险率增加至1.339倍(OR=1.339；95%CI：1.051-1.706；P=0.017)。在男性IS组与男性对照组构建6个单倍体型,GGGT单倍型在IS组中的分布频率明显高于对照组,携带GGGT单倍型的个体,患缺血性卒中的风险率增加至1.545倍(OR=1.545；95%CI：1.144-2.087；P=0.004)。在女性IS组与女性对照组构建8个单倍型,两组间比较无统计学差异。
5、CYP4A11基因rs9333025位点的多态性在IS组与对照组的频率分布：rs9333025位点IS组与对照组比较,G／G基因型的频率高于对照组,而G/A+A/A的频率低于对照组,基因型频率比较χ2=9.311,P=0.02,OR=1.698,95%CI1.207-2.389。应用logistic回归分析校正传统危险因素(高血压、糖尿病、高脂血症、吸烟等)后GG基因型频病例组和对照组比较差异仍然有统计学意义,χ2=6.715,P=0.01,OR=1.721,95%CI：1.141-2.594。
6、LTC4S基因rs730012位点多态性在对照组与IS组中频率分布：IS组与对照组比较C／C基因型的频率明显高于对照组,A／C,A／A基因型的频率均低于对照组,基因频率比较χ2=3.41,P=0.011,OR=3.41,95%CI：1.257-9.245；A与C等位基因频率比较χ2=11.057,df=1,OR=1.680,95%CI=1.235～2.286,P=0.001。应用Logistic回归分析校正后仍有统计学意义(OR=0.881；95%CI：0.786-0.989；P=0.031)。将IS组按不同病因分为大血管组(血栓性脑梗死组)和小血管组(腔隙性脑梗死组)后,大血管组与对照组比较C／C基因型的频率明显低于对照组。
7、LTC4S基因rs331446827位点多态性在对照组与IS组中频率分布：rs331446827位点C／C基因型的频率IS组与对照组比较无统计学意义(P>0.05)。
结论
1、CYP4F2基因rs2108622位点GG基因型可能是中国北方汉族人群男性缺血性卒中的独立的危险因素,G等位基因可以增加男性患缺血性脑卒中的遗传易感性。
2、CYP4F2基因rs3093100、rs3093105、rs3093135以及rs1558139位点的基因多态性与缺血性脑卒中无关。
3、CYP4F2基因的GGGT单倍型可能是IS的风险单倍型。
4、CYP4A11基因rs9333025位点GG基因型与IS具有相关性,G等位基因增加缺血性脑卒中的遗传易感性
5、LTC4S基因rs730012位点C／C基因型可能具有保护作用的基因。
6、LTC4S基因rs3776924位点的多态性与IS无关。
Effect of Polymorphisms of CYP4F2、CYP4A11 and LTC4S Gene on Ischemic Stroke
Objective
Cerebrovascular disease(CVD) is one of the three major causes of death, and is harmful to human health. Ischemic stroke(IS) of incidence of cerebrovascular disease accounted for 80%.IS is a heterogeneous multifactorial disorder. In addition to conventional risk factors such as hypertension, diabetes mellitus, and smoking, evidence from animals and clinical and epidemiological studies have repeatedly supported the likelihood of a genetic contribution to CI susceptibility. Epidemiological data provide substantial evidence for a genetic component to the disorder. Identifying accurately its genetic determinants is a key issue in order to improve diagnosis and treatment strategies and to reduce stroke's huge public health burden.
Arachidonic acid (AA) is the most abundant substances in the human body which is one of the important precursors of cardiovascular active substances. It has been reported that 20-hydroxyeicosatetraenoic acid (HETE) plays an important role in the pathogenesis of ischemic stroke.20-HETE is a metabolite of arachidonic acid (AA) generated by the CYP4F2 and CYP4A11 subfamily of cytochrome P450 (CYP450) and plays a significant role in the regulation of vascular tone in renal, cerebral, coronary, and skeletal muscle arterioles, and in the pulmonary circulation. CYP450 enzymes form the 3rd pathway of arachidonic acid (AA) metabolize AA. CYP450-derived arachidonic acid metabolites play a role in the modulation of cerebrovascular pathology and physiology. CYP4F2 and CYP4A11 are members of the family of CYP450 enzymes, and mainly act as enzymes that is involved not only in the metabolism of leukotriene B4 (LTB4), but also 20-HETE. It has been reported that cerebral infarction is associated with the polymorphism of rs2108622.However the association results of these candidate genes in different regions and for different ethnic population have not been effectively reapeated and confirmed. In view of northern Chinese population with higher incidence of IS, it is necessary to carry out an association study of candidated susceptible genes aimed at northern China region Han population IS.
Atherosclerosis is an important pathophysiological basis of IS, and inflammatory reaction process is of great significance in atherosclerosis formation, Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Studies in animals and in vitro suggest that both LTB4 and cysteinyl leukotrienes participate in the development of atherosclerotic lesions. LTC4 synthase lead LTA4 to LTC4, D4 and E4 (collectively referred to as the cysteinyl-LTs). so our study selected inflammation-related LTC4 synthase gene. By introducing candidate genes case-control association analysis, we mesured LTC4 synthase gene allele frequencies between IS group. So we can provide IS molecular epidemiology data for comprehensively understanding IS potential genetic mechanisms and more early IS molecular biology diagnosis indicators.
Materials and methods
A case-control design was introduced. The subjects of IS group were consecutively recruited from northern China region patients with a total of 302 cases male 193,female 109, aged 40-80 years old, Han nationality, no consanguinity with each other. The controls matched by age, sex, and ethnic orign were recruited from the same patients geographic region, with a total of 350 cases, male 212, female 138. Accordting to the different causes the patients were divided into two subgroups:the large vessels group (thrombotic cerebral infarction group) and the small vessels group(lacunar infarction group). CYP4F2 gene rs2108622, rs3093100, rs3093105, rs3093135; CYP4A11 gene rs9333025 and LTC4S gene rs73002 SNPs were genotyped by polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP) analysis.CYP4F2 gene rs1558139 and LTC4S gene rs331446829 SNPs were genotyped by means of Matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF) primer extension reaction. Genotyping results were confirmed by squencing method. SPSS 13.0 statistical software was used for data processing. Continuous variables were expressed as mean±SE and were assessed by One-Way ANOVA. Genotype and allele frequencies were calculated for control group and each of the patient groups. Univariate comparisons of allele and genotype distributions were done usingχ2 test. Theχ2 goodness of fit test was used to test for deviation of genotype distribution from Hardy-Weinberg equilibrium. Conditional Logistic Regression adjusted for IS traditional risk factors including age, blood pressure, blood sugar, blood lipids and smoking. The influence of CYP4F2、CYP4A11 and LTC4S gene polymorphisms on IS was indicated by odds ratio(OR) and 95% confidenc(CI) with P＜0.05 as significant criteria. Haplotype-based analysis was infered by using Shesis online-software. The synergistic action of CYP4F2 gene、CYP4Allgene and LTC4S gene for IS was analysed by UNPHASED 3.0.7 version software.
Results
1. The genotype frequencies of all SNPs conformed to the expectations of Hardy-Weinberg equilibrium(P＞0.05). It was suggested that the selected samples could represent the population and were suitable for genetic analysis.
2. CYP4F2 gene rs2108622 SNP frequencies distributions among the patients and the controls:rs2108622 G/G genotyp frequencies of the male IS group were higher than the male control group (OR=2.53; 95%CI:1.15-5.56; P=0.018), and after logistic regression the differece was still significant OR=1.78; 95%CI:1.120～2.854; P=0.015 (GG vs AA+GA)), (OR=3.14; 95%CI 1.283-7.71; P=0.012(GG+GA vs AA)). G allele frequencies of the male IS group were higher than the male control group (OR=1.48; 95%CI:1.09-2.02; P=0.013).There were no significant differences with regard to G/G genotyp frequencies between the IS patients and the control and female.
3. CYP4F2 gene rs3093100、rs3093105、rs3093135 and rs1558139 SNPs frequencies distributions among the patients and the controls:There were no significant differences with regard to rs3093100 C/C genotyp frequencies between the IS patients and the control,males and females (P＞0.05). There were no significant differences with regard to rs3093105 T/T genotyp frequencies between the IS patients and the control,males and females (P＞0.05). There were no significant differences with regard to rs3093135 T/T genotyp frequencies between the IS patients and the control,males and females (P＞0.05). There were no significant differences with regard to rs1558139 G/G genotyp frequencies between the IS patients and the control,males and females (P＞0.05).
4. CYP4F2 gene haplotype frequencies among the patients and the controls:5 haplotypes were identified among the patients and the controls, GGGT haplotype frequencies of the IS group were higher than the control group (OR= 1.339; 95%CI: 1.051-1.706; P=0.017);6 haplotypes were identified among the male patients and the male controls, the GGGT haplotype frequencies of the male cases were higher than the male control group (OR= 1.545; 95%CI:1.144-2.087; P=0.004); 8 haplotypes were identified among the female patients and the female, significant differences of all the haplotypes were not observed in the female IS group and the female control group (P＜0.05).
5. CYP4A11 gene rs9333025 SNP frequencies distributions among the patients and the controls:rs9333025G/G genotyp frequencies of IS group were higher than the control group(P=0.02, OR=1.698,95%CI:1.207-2.389), and after logistic regression the differece was still significant(P=0.01,OR=1.721,95%CI:1.141-2.594)rs9333025 G allele frequencies of the IS group were higher than the control group (OR=1.661; 95%CI:1.22-2.24; P=0.001)
6. LTC4S gene rs730012 SNP frequencies distributions among the patients and the controls:rs730012 C/C genotyp frequencies of the control group were lower than the IS group (OR=3.41; 95%CI:1.257-9.245;P=0.011), and after logistic regression the differece was still significant (OR=0.892; 95%CI:0.797-0.998; P=0.047)
7. LTC4S gene rs331446827 SNP frequencies distributions among the patients and the controls:There were no significant differences with regard to rs331446827 A/A genotyp frequencies between the IS patients and the control. Conclusions
1、CYP4F2 gene rs2108622 G/G genotype might be the independent risk factors of northern China region han population ischemic strke, and its risk mainly came from G allele.
2、There were no association between the polymorphisms of rs3093100、 rs3093105、rs3093135 and rsl558139 and northern China region han population ischemic strke.
3、CYP4F2 gene GCGA haplotype might be at-risk haplotype of IS
4、CYP4A11 gene rs9333025 G/G genotype might be associated with IS.G allele might be risk allele
5、LTC4S gene rs730012 C/C genotype might be protective.
6、There was no association between the SNP of rs331446827 and IS.
引文
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