淋巴毒素α与急性冠脉综合征发病关系的研究
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摘要
目的：检测急性冠脉综合征患者及对照组淋巴毒素α(LTA)C804A、A252G基因多态性，并测定LTA、髓过氧化物酶(MPO)、肿瘤坏死因子(TNFα)、细胞间黏附因子(ICAM-1)水平，分析LTA804位点、LTA252位点基因突变与冠状动脉病变范围及炎症因子表达的相关性，进而探讨遗传因素、炎症反应与急性冠脉综合征发病关系。
方法：选择2007年9月至2008年12月，天津市第一中心医院心内科收治的急性冠脉综合征组病人106例，对照组80例，入选的所有病人入院后均接受冠状动脉造影检查，不稳定心绞痛或急性心肌梗塞病人的诊断均依据ACC／AHA指南。记录患者下列临床资料：年龄、性别、吸烟史、饮酒史、高血压史、冠心病家族史、甘油三脂、总胆固醇、低密度脂蛋白、高密度脂蛋白、尿酸、空腹血糖水平等。根据冠状动脉造影结果分为急性冠脉综合征(ACS)组106例和对照组80例，ACS组根据其类型又分为不稳定型心绞痛(UAP)组和急性心肌梗塞(AMI)组。用酶联免疫吸附实验测定(ELISA)淋巴毒素α(LTA)、肿瘤坏死因子-α(TNF-α)、髓过氧化物酶(MPO)、细胞间黏附因子(ICAM-1)水平，用DNA试剂盒提取DNA，利用多聚酶链反应(PCR)及琼脂糖凝胶电泳分析淋巴细胞毒素-α(LTA-α)基因C804A、A252G的基因多态性并进行测序。应用SPSS13．0数据统计软件对实验数据进行统计学分析。两组间定量资料进行正态性检验，正态分布资料采用均数±标准差((?)±s)表示，两样本均数比较采用t检验，多样本均数比较应用方差分析，组间比较采用q检验。计数资料以百分数表示，例数及率的比较采用x~2检验。以P＜0．05为差异有统计学意义。
结果：急性冠脉综合征组测定的TNF-α、MPO、LTA、ICAM-1水平高于对照组，其中AMI组TNF-α、ICAM-1水平高于UAP组(P＜0．05)。急性冠脉综合征组不同病变程度的TNF-α水平差异有统计学意义，多支病变高于单支病变(P＜0．01)。UAP组与AMI组测定的MPO、LTA无差异。急性冠脉综合征组不同病变范围测得的MPO、LTA、ICAM-1水平无显著性差异(P＞0．05)。LTA804位点存在CC、CA、AA3种基因型。急性冠脉综合征组与对照组LTA804位点基因型、等位基因频率比较无统计学差异(P＞0．05)。急性冠脉综合征组中不同病变程度的LTA804位点基因型发生的总体概率、等位基因频率无统计学差异(P＞0．05)，但多支病变中杂合突变CA、纯合突变AA型TNF-α水平高于野生型CC(P＜0．05)。LTA252位点存在AA、AG、GG 3种基因型。急性冠脉综合征组与对照组LTA252位点基因型、等位基因频率比较有显著性差异。急性冠脉综合征组以AG型所占的百分比最高，较对照组为多。A与G两个等位基因频率有差别(P＜0．05)。急性冠脉综合征组中不同病变程度的LTA252位点基因型发生的总体概率、等位基因频率无显著性差别(P＞0．05)。对照组、急性冠脉综合征组LTA C804A、A252G不同基因型TNF-α、MPO、LTA、ICAM-1水平无统计学差异(P＞0．05)。
结论：1、急性冠脉综合征组TNF-α、MPO、LTA、ICAM-1水平显著高于对照组，其中心肌梗塞组TNF-α、ICAM-1水平明显高于不稳定型心绞痛组。TNF-α水平与病变范围有关，说明急性冠脉综合征发生时，动脉粥样斑块破裂伴有多种炎性因子的大量释放，TNF-α、ICAM-1可能与动脉粥样斑块的稳定程度密切相关。TNF-α、sICAM-1水平可作为急性冠脉综合征发生及转归的指标。
2、急性冠脉综合征组与对照组LTA基因C804A，CC、CA、AA基因型及等位基因C、A频率无显著差异，因此尚不能说明LTAC804A基因突变是冠心病的危险因素。
3、急性冠脉综合征组与对照组比较，LTA基因A252G，AA、AG、GG基因型有显著性差异，急性冠脉综合征组以AG型所占的百分比最高；两组在A与G两个等位基因频率上有差别。UAP组和AMI组无显著差异。这些结果提示LTA A252G基因多态性与冠心病有关，LTAA252G基因突变可能是冠心病的危险因素之一。
4、对照组LTA基因C804A，CC、CA、AA各基因型TNF-α水平无显著差异；而在急性冠脉综合征组，LTA基因C804ACC、CA、AA基因型，在单支病变无显著差异，在多支病变突变型(CA型和AA型)TNF-α水平较野生型(CC型)显著升高，说明在急性冠脉综合征病人尤其是冠状动脉病变较重(二支以上)的病人，基因突变可影响炎症因子分泌，促进TNF-α释放，加重病变。
Objective:To investigate lymphotoxin-α(LTA) gene C804A and A252Gpolymorphism,LTA,tumor necrosis factor alpha (TNF-α),Myeloperoxidase (MPO)and intercellular adhesion molecule (ICAM-1) in acute coronary syndrome group andcontrol group.And,to analyze the relationship between LTA804,LTA252 site genesmutation with inflammation factor gene expression and the extent of coronary arterydisease.To disclose an inherit cause and inflammatory response related to thepathogenesis of ACS.
Methods:We select 186 patients who were hospitalized in Tianjin first centralhospital cardiovascular department from Sep 2007 and Dec 2008.Their clinicinformation was recorded,such as gender,age,smoking,drinking,CHD familyhistory,diabetes history,triglyceride,total cholesterol,low-density lipoproteincholesterol,high density lipoprotein cholesterol,uric acid,fasting plasma glucose,etc.And,all patients were undergone with coronary angiography.Diagnosis of unstableangina pectoris(UAP) or acute myocardial infarction(AMI) was performed byaccording to ACC/AHA Guidelines.According to the results of coronary angiography,186 patients were divided into ACS group (106 cases) and control group (80 cases).ACS group was divided into UAP and AMI subgroup.Their serum levels of tumornecrosis factor-α,lymphotoxin-α,Myeloperoxidase and intercellar adhesion moleculewere measured by enzyme-linked immunosorbent assay (ELISA).DNA was extractedwith AxyPrep DNA reagent.The mutation of the LTA 804C→A,252A→G transitionwas examined by polymerase chain reaction and identified with agarose gelelectrophoresis.Using statistic software SPSS 13.0 to analyze the data,Chi square testwere used to compare numeration data between two groups.Measurement data wereexpressed as mean±SD,followed F analysis,t or q test was used to comparemeasurement data between groups.The level of significance was set at P＜0.05.
Results:The level of TNF-α,MPO,LTA and ICAM-1 in ACS group weresignificantly higher than control group (P＜0.01).The level of TNF-αand ICAM-1 inacute myocardial infarction (AMI) group were higher than that in unstable anginapectoris (UAP) group.There were no differences of MPO and LTA between AMI group and UAP group.The serum level of TNF-αwas associated with the degree ofcoronary lesion in ACS group.The levels of TNF-αin two or three vessels coronarylesion group were significantly higher than that in one vessel coronary lesion group.There were no differences of MPO,LTA and ICAM-1 in ACS group with thedifferent coronary lesion.There were three kinds of genotypes,CC,AA and CA inLTA gene 804.LTA gene C804A genotype frequencies and distributions wereequilibrium in ACS group and control group.The levels of TNF-αwith differentgenotypes had no statistic difference in ACS group with the different coronary lesion.The plasma levels of TNF-αwith mutation genotypes were significantly differentboth in two vessels and three vessels coronary lesion of ACS group.The levels ofTNF-αin mutation genotypes (CA and AA) were higher than that in CC type.Therewere three kinds of genotypes AA,AG and GG in LTA gene 252.LTA gene A252Ggenotype frequencies and distributions were different in ACS group and control group.Genotype of AG are highest in ACS group.There were no differences of LTA geneA252G genotype frequencies and distributions in patients with different coronarylesions of ACS group.There were no differences of TNF-α,MPO,LTA and ICAM-1with different genotype of LTA gene C804A and A252G in ACS and control group.
Conclusion:1、The levels of TNF-α,MPO,LTA and ICAM-1 in ACS group werehigher then that in control group.The levels of TNF-αand ICAM-1 in AMI groupwere higher than that in UAP group.TNF-αwere related with coronary lesionextension in ACS group.TNF-α、ICAM-1 may be the marker of plaque rupture,theyalso had influence on ACS development and prognosis.2、There were no differencesof LTA gene C804 genotype frequencies and distributions in ACS group and controlgroup.Interaction was not presented between LTA gene C804A mutation and ACS.3、The mutation of LTA gene A252G was associated with ACS.May be it was one of therisk factor of coronary heart disease.4、The more severity coronary lesion was inmutation LTA gene C804A,the more higher levels of TNF-αin ACS group.LTA geneC804A mutation may promote inflammation factors release.
方法：选择2007年9月至2008年12月，天津市第一中心医院心内科收治的急性冠脉综合征组病人106例，对照组80例，入选的所有病人入院后均接受冠状动脉造影检查，不稳定心绞痛或急性心肌梗塞病人的诊断均依据ACC／AHA指南。记录患者下列临床资料：年龄、性别、吸烟史、饮酒史、高血压史、冠心病家族史、甘油三脂、总胆固醇、低密度脂蛋白、高密度脂蛋白、尿酸、空腹血糖水平等。根据冠状动脉造影结果分为急性冠脉综合征(ACS)组106例和对照组80例，ACS组根据其类型又分为不稳定型心绞痛(UAP)组和急性心肌梗塞(AMI)组。用酶联免疫吸附实验测定(ELISA)淋巴毒素α(LTA)、肿瘤坏死因子-α(TNF-α)、髓过氧化物酶(MPO)、细胞间黏附因子(ICAM-1)水平，用DNA试剂盒提取DNA，利用多聚酶链反应(PCR)及琼脂糖凝胶电泳分析淋巴细胞毒素-α(LTA-α)基因C804A、A252G的基因多态性并进行测序。应用SPSS13．0数据统计软件对实验数据进行统计学分析。两组间定量资料进行正态性检验，正态分布资料采用均数±标准差((?)±s)表示，两样本均数比较采用t检验，多样本均数比较应用方差分析，组间比较采用q检验。计数资料以百分数表示，例数及率的比较采用x~2检验。以P＜0．05为差异有统计学意义。
结果：急性冠脉综合征组测定的TNF-α、MPO、LTA、ICAM-1水平高于对照组，其中AMI组TNF-α、ICAM-1水平高于UAP组(P＜0．05)。急性冠脉综合征组不同病变程度的TNF-α水平差异有统计学意义，多支病变高于单支病变(P＜0．01)。UAP组与AMI组测定的MPO、LTA无差异。急性冠脉综合征组不同病变范围测得的MPO、LTA、ICAM-1水平无显著性差异(P＞0．05)。LTA804位点存在CC、CA、AA3种基因型。急性冠脉综合征组与对照组LTA804位点基因型、等位基因频率比较无统计学差异(P＞0．05)。急性冠脉综合征组中不同病变程度的LTA804位点基因型发生的总体概率、等位基因频率无统计学差异(P＞0．05)，但多支病变中杂合突变CA、纯合突变AA型TNF-α水平高于野生型CC(P＜0．05)。LTA252位点存在AA、AG、GG 3种基因型。急性冠脉综合征组与对照组LTA252位点基因型、等位基因频率比较有显著性差异。急性冠脉综合征组以AG型所占的百分比最高，较对照组为多。A与G两个等位基因频率有差别(P＜0．05)。急性冠脉综合征组中不同病变程度的LTA252位点基因型发生的总体概率、等位基因频率无显著性差别(P＞0．05)。对照组、急性冠脉综合征组LTA C804A、A252G不同基因型TNF-α、MPO、LTA、ICAM-1水平无统计学差异(P＞0．05)。
结论：1、急性冠脉综合征组TNF-α、MPO、LTA、ICAM-1水平显著高于对照组，其中心肌梗塞组TNF-α、ICAM-1水平明显高于不稳定型心绞痛组。TNF-α水平与病变范围有关，说明急性冠脉综合征发生时，动脉粥样斑块破裂伴有多种炎性因子的大量释放，TNF-α、ICAM-1可能与动脉粥样斑块的稳定程度密切相关。TNF-α、sICAM-1水平可作为急性冠脉综合征发生及转归的指标。
2、急性冠脉综合征组与对照组LTA基因C804A，CC、CA、AA基因型及等位基因C、A频率无显著差异，因此尚不能说明LTAC804A基因突变是冠心病的危险因素。
3、急性冠脉综合征组与对照组比较，LTA基因A252G，AA、AG、GG基因型有显著性差异，急性冠脉综合征组以AG型所占的百分比最高；两组在A与G两个等位基因频率上有差别。UAP组和AMI组无显著差异。这些结果提示LTA A252G基因多态性与冠心病有关，LTAA252G基因突变可能是冠心病的危险因素之一。
4、对照组LTA基因C804A，CC、CA、AA各基因型TNF-α水平无显著差异；而在急性冠脉综合征组，LTA基因C804ACC、CA、AA基因型，在单支病变无显著差异，在多支病变突变型(CA型和AA型)TNF-α水平较野生型(CC型)显著升高，说明在急性冠脉综合征病人尤其是冠状动脉病变较重(二支以上)的病人，基因突变可影响炎症因子分泌，促进TNF-α释放，加重病变。
Objective:To investigate lymphotoxin-α(LTA) gene C804A and A252Gpolymorphism,LTA,tumor necrosis factor alpha (TNF-α),Myeloperoxidase (MPO)and intercellular adhesion molecule (ICAM-1) in acute coronary syndrome group andcontrol group.And,to analyze the relationship between LTA804,LTA252 site genesmutation with inflammation factor gene expression and the extent of coronary arterydisease.To disclose an inherit cause and inflammatory response related to thepathogenesis of ACS.
Methods:We select 186 patients who were hospitalized in Tianjin first centralhospital cardiovascular department from Sep 2007 and Dec 2008.Their clinicinformation was recorded,such as gender,age,smoking,drinking,CHD familyhistory,diabetes history,triglyceride,total cholesterol,low-density lipoproteincholesterol,high density lipoprotein cholesterol,uric acid,fasting plasma glucose,etc.And,all patients were undergone with coronary angiography.Diagnosis of unstableangina pectoris(UAP) or acute myocardial infarction(AMI) was performed byaccording to ACC/AHA Guidelines.According to the results of coronary angiography,186 patients were divided into ACS group (106 cases) and control group (80 cases).ACS group was divided into UAP and AMI subgroup.Their serum levels of tumornecrosis factor-α,lymphotoxin-α,Myeloperoxidase and intercellar adhesion moleculewere measured by enzyme-linked immunosorbent assay (ELISA).DNA was extractedwith AxyPrep DNA reagent.The mutation of the LTA 804C→A,252A→G transitionwas examined by polymerase chain reaction and identified with agarose gelelectrophoresis.Using statistic software SPSS 13.0 to analyze the data,Chi square testwere used to compare numeration data between two groups.Measurement data wereexpressed as mean±SD,followed F analysis,t or q test was used to comparemeasurement data between groups.The level of significance was set at P＜0.05.
Results:The level of TNF-α,MPO,LTA and ICAM-1 in ACS group weresignificantly higher than control group (P＜0.01).The level of TNF-αand ICAM-1 inacute myocardial infarction (AMI) group were higher than that in unstable anginapectoris (UAP) group.There were no differences of MPO and LTA between AMI group and UAP group.The serum level of TNF-αwas associated with the degree ofcoronary lesion in ACS group.The levels of TNF-αin two or three vessels coronarylesion group were significantly higher than that in one vessel coronary lesion group.There were no differences of MPO,LTA and ICAM-1 in ACS group with thedifferent coronary lesion.There were three kinds of genotypes,CC,AA and CA inLTA gene 804.LTA gene C804A genotype frequencies and distributions wereequilibrium in ACS group and control group.The levels of TNF-αwith differentgenotypes had no statistic difference in ACS group with the different coronary lesion.The plasma levels of TNF-αwith mutation genotypes were significantly differentboth in two vessels and three vessels coronary lesion of ACS group.The levels ofTNF-αin mutation genotypes (CA and AA) were higher than that in CC type.Therewere three kinds of genotypes AA,AG and GG in LTA gene 252.LTA gene A252Ggenotype frequencies and distributions were different in ACS group and control group.Genotype of AG are highest in ACS group.There were no differences of LTA geneA252G genotype frequencies and distributions in patients with different coronarylesions of ACS group.There were no differences of TNF-α,MPO,LTA and ICAM-1with different genotype of LTA gene C804A and A252G in ACS and control group.
Conclusion:1、The levels of TNF-α,MPO,LTA and ICAM-1 in ACS group werehigher then that in control group.The levels of TNF-αand ICAM-1 in AMI groupwere higher than that in UAP group.TNF-αwere related with coronary lesionextension in ACS group.TNF-α、ICAM-1 may be the marker of plaque rupture,theyalso had influence on ACS development and prognosis.2、There were no differencesof LTA gene C804 genotype frequencies and distributions in ACS group and controlgroup.Interaction was not presented between LTA gene C804A mutation and ACS.3、The mutation of LTA gene A252G was associated with ACS.May be it was one of therisk factor of coronary heart disease.4、The more severity coronary lesion was inmutation LTA gene C804A,the more higher levels of TNF-αin ACS group.LTA geneC804A mutation may promote inflammation factors release.
引文
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