乙醛脱氢酶2活性水平及基因型与冠心病的相关性研究
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摘要
冠状动脉粥样硬化性心脏病（coronary atherosclerotic heart disease，CAD）是指冠状动脉粥样硬化使血管腔狭窄或阻塞，导致心肌缺血、缺氧而引起的心脏病，它和冠状动脉功能性改变（痉挛）一起，统称冠状动脉性心脏病，简称冠心病（coronary heart disease，CHD）。冠心病是威胁人类健康、影响生活质量的常见疾病。目前，有研究显示乙醛脱氢酶2（aldehyde dehydrogenase2，ALDH2）不仅是酒精代谢过程中的关键酶，而且是体内重要的抗氧化应激分子，可减少乙醛及其他脂肪族醛的细胞毒性，对心脏有保护作用。
ALDH2由ALDH2基因编码，有学者认为ALDH2基因参与了冠心病的发生与发展。ALDH2基因具有单核苷酸多态性，其中研究最多的是Glu504Lys多态性位点（又称rs671），该位点发生碱基置换，即鸟嘌呤（G，野生型）被腺嘌呤（A，突变型）替代。所以，ALDH2有两个等位基因：G等位基因（ALDH2*1）和A等位基因（ALDH2*2），导致人群中该酶基因型有3种情况：野生纯合型（GG型又称ALDH2*1/*1）、突变杂合型（GA型又称ALDH2*1/*2）和突变纯合型（AA型又称ALDH2*2/*2）。日本学者发现ALDH2突变基因型是日本男性心肌梗死（myocardial infarction，MI）的独立危险因素。
硝酸酯类药物是心血管领域中应用较早且应用较广泛的药物，但是硝酸酯类药物的生物转化机制仍未被完全阐明。最近，研究人员发现ALDH2对硝酸甘油发挥临床疗效具有一定影响，但是关于ALDH2不同基因型患者与硝酸酯类药物尤其是单硝酸异山梨酯治疗心绞痛临床疗效之间的研究相对较少。
本研究拟从ALDH2活性水平及基因型方面，探讨ALDH2与冠心病特别是心肌梗死的相关性，以及ALDH2不同基因型患者临床应用硝酸甘油和单硝酸异山梨酯有效性之间的关系，为冠心病临床评估、发病机制以及药物治疗提供一定的理论依据和新的思路。
第一部分乙醛脱氢酶2活性水平与冠心病的相关性研究
目的：探讨乙醛脱氢酶2活性水平与冠心病之间的关系。
方法：选择2011年1月至2012年12月在唐山工人医院心内科住院的患者共191例，其中心绞痛患者62例，急性心肌梗死（acute myocardialinfarction，AMI）患者64例，对照者65例。记录所有研究对象临床基本资料，包括：年龄、性别、吸烟史、饮酒史、高血压病史和糖尿病病史，测量受试对象身高（Height，H）、体重（Weight，W），计算体重指数（body mass index，BMI）。入选研究对象于入院第二天清晨采集外周静脉血，采用血液ALDH2活性比色法定量检测试剂盒检测ALDH2活性水平；同时采用酶法测定总胆固醇（total cholesterol，TC）、甘油三酯（triglycerides，TG）、高密度脂蛋白胆固醇（high density lipoproteincholesterol，HDL-C）和低密度脂蛋白胆固醇（low density lipoproteincholesterol，LDL-C）。采用SPSS16.0软件进行数据统计，对三组患者临床基本资料、ALDH2活性水平进行比较，采用相关分析分析血浆ALDH2活性水平与BMI、TC、TG、HDL-C、LDL-C水平的相关性。
结果：
（1）对照组、心绞痛组、AMI组ALDH2活性水平分别为（23.76±6.31）U/L、（22.37±6.03）U/L、（21.14±5.76）U/L，三组活性水平依次降低，但差异无统计学意义（p＞0.05）。
（2）相关分析显示对照组、心绞痛组、AMI组ALDH2水平与BMI、TC、TG、HDL-C、LDL-C水平均无相关性（p＞0.05）。
结论：对照组、心绞痛组和AMI组ALDH2活性水平依次下降，但差异无统计学意义，ALDH2水平与BMI、TC、TG、HDL-C、LDL-C水平无相关性，提示ALDH2活性水平与冠心病病情严重程度无关，ALDH2不能作为判断冠心病病情严重程度的预测指标。
第二部分乙醛脱氢酶2基因型与急性心肌梗死的相关性研究
目的：探讨乙醛脱氢酶2基因型与急性心肌梗死之间的相关性。
方法：选择2011年1月至2012年12月在唐山工人医院心内科住院诊断为急性心肌梗死（AMI）患者210例和对照者221例。记录所有研究对象临床基本资料，包括：年龄、性别、吸烟史、饮酒史、高血压病史和糖尿病病史，测量受试对象身高（H）、体重（W），计算体重指数（BMI）。采用酶法测定总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）。采集所有受试者外周静脉血提取基因组DNA，采用测序方法检测ALDH2基因Glu504Lys位点多态性。所有入选患者均进行冠状动脉造影检查，根据病变累及支数，分为单支病变、双支病变和三支病变。采用SPSS16.0软件进行数据统计，对AMI组和对照组临床基本资料、基因型频率和等位基因频率进行比较，并进一步对研究人群的饮酒情况和年龄情况进行分层分析，采用多因素Logistic回归分析判断疾病危险因素作用的大小，计算比数比（Odds Ratio，OR）和95%可信区间（95%Confidence Index，95%CI）。
结果：
（1）AMI组和对照组ALDH2基因型分布均符合Hardy-Weinberg平衡。
（2）AMI组GG、GA、AA基因型频率分别为：50.48%、43.81%、5.71%，对照组GG、GA、AA基因型频率分别为：69.68%、28.05%、2.26%，两组基因型分布差异有统计学意义（p＜0.001）。AMI组G等位基因频率低于对照组（72.38%vs.83.71%），A等位基因频率高于对照组（27.62%vs.16.29%），两组比较差异有统计学意义（p＜0.05）。
（3）以有无AMI为因变量，将年龄、性别、吸烟史、饮酒史、高血压病史、糖尿病病史、BMI、TC、TG、HDL-C、LDL-C、ALDH2基因型引入Logistic回归模型，多因素Logistic回归分析显示ALDH2GA+AA突变基因型是AMI的危险因素（OR=1.300，95%CI：1.035-1.634，p=0.0243）。
（4）AMI组ALDH2不同基因型与冠状动脉病变支数无明显相关性（p＞0.05）。
（5）根据研究人群的饮酒情况进行分层分析，在非饮酒人群中多因素Logistic回归分析显示，GA+AA突变基因型是AMI的危险因素（OR=1.791，95%CI：1.005-3.189，p=0.048）；在饮酒人群中Logistic回归分析显示，GA+AA突变基因型不是AMI的危险因素（OR=1.041，95%CI：0.974-1.113，p=0.2327）。
（6）根据研究人群的年龄进行分层分析，多因素Logistic回归分析显示，在早发人群（男性＜55岁，女性＜65岁）中未发现携带GA+AA突变基因型个体患AMI的风险增加（OR=1.030，95%CI：0.983-1.079，p=0.2097），提示ALDH2GA+AA突变基因型不是早发AMI的危险因素；在晚发人群（男性≥55岁，女性≥65岁）中发现携带GA+AA突变基因型个体患AMI的风险增加（OR=1.424，95%CI:1.029-1.969，p=0.0329）。
结论：
（1）ALDH2GA+AA突变基因型是AMI的危险因素。
（2）AMI患者ALDH2基因型与冠状动脉病变支数无相关性。
（3）分层分析显示，ALDH2GA+AA突变基因型是非饮酒人群AMI的危险因素，而不是饮酒人群AMI的危险因素；ALDH2GA+AA突变基因型是晚发AMI的危险因素，而不是早发AMI的危险因素。
第三部分乙醛脱氢酶2不同基因型心绞痛患者应用硝酸甘油和单硝酸异山梨酯临床疗效的相关性研究
目的：探讨乙醛脱氢酶2不同基因型心绞痛患者应用硝酸甘油和单硝酸异山梨酯临床疗效之间的关系。
方法：选择2011年1月至2012年12月在唐山工人医院心内科住院诊断为冠心病心绞痛患者395例，将患者随机分为2组，硝酸甘油组201例，单硝酸异山梨酯组194例，记录所有研究对象临床基本资料，包括：年龄、性别、吸烟史、饮酒史、高血压病史和糖尿病病史等，测量受试对象身高（H）、体重（W），计算体重指数（BMI）。采用酶法测定总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）。采集所有受试者外周静脉血提取基因组DNA，采用测序方法检测ALDH2基因Glu504Lys位点多态性。所有研究对象用药期间，定期做心电图及肝肾功能检查，观察两组内不同基因型患者心绞痛发作频率、程度、持续时间，对比静息心电图ST-T变化，并记录用药期间不良反应的发生情况，比较不同患者的临床症状疗效和心电图疗效。
结果：
（1）硝酸甘油组和单硝酸异山梨酯组ALDH2基因型分布无明显差异（p＞0.05）。
（2）应用硝酸甘油的临床症状疗效：ALDH2GG野生基因型患者显效40例，有效55例，无效40例；ALDH2GA+AA突变基因型患者显效17例，有效20例，无效29例。GG野生基因型患者、GA+AA突变基因型患者应用硝酸甘油的临床症状疗效差异无统计学意义（p＞0.05）。
应用硝酸甘油的心电图疗效：ALDH2GG野生基因型患者显效28例，有效56例，无效51例；ALDH2GA+AA突变基因型患者显效10例，有效21例，无效35例。GG野生基因型患者、GA+AA突变基因型患者应用硝酸甘油的心电图疗效差异无统计学意义（p＞0.05）。
（3）应用单硝酸异山梨酯的临床症状疗效：ALDH2GG野生基因型患者显效47例，有效73例，无效12例；ALDH2GA+AA突变基因型患者显效20例，有效31例，无效11例。GG野生基因型患者、GA+AA突变基因型患者应用单硝酸异山梨酯的临床症状疗效差异无统计学意义（p＞0.05）。
应用单硝酸异山梨酯的心电图疗效：ALDH2GG野生基因型患者显效41例，有效67例，无效24例；ALDH2GA+AA突变基因型患者显效18例，有效26例，无效18例。GG野生基因型患者、GA+AA突变基因型患者应用单硝酸异山梨酯的心电图疗效差异无统计学意义（p＞0.05）。
（4）ALDH2GG野生基因型患者应用单硝酸异山梨酯治疗心绞痛的临床症状疗效、心电图疗效优于硝酸甘油，差异有统计学意义（p＜0.05）；ALDH2GA+AA突变基因型患者应用单硝酸异山梨酯治疗心绞痛的临床症状疗效、心电图疗效也优于硝酸甘油，差异有统计学意义，（p＜0.05）。
结论：
（1）ALDH2GG野生基因型患者与GA+AA突变基因型患者应用硝酸甘油治疗心绞痛的临床疗效无差异。
（2）ALDH2GG野生基因型患者与GA+AA突变基因型患者应用单硝酸异山梨酯治疗心绞痛的临床疗效无差异。
（3）无论是ALDH2GG野生基因型患者还是GA+AA突变基因型患者，应用单硝酸异山梨酯治疗心绞痛的临床疗效均优于硝酸甘油，且不良反应小，安全性高。
Coronary atherosclerotic heart disease (CAD) refered to coronaryatherosclerosis caused vascular stenosis or obstruction, leading to myocardialischemia, hypoxia, together with coronary functional change (spasm) werecalled coronary heart disease (CHD). CHD was a common disease having aserious threat to health, affecting the quality of life. Currently, studies haveshown that aldehyde dehydrogenase2(ALDH2) was not only one of the keyenzyme in the process of alcohol metabolism, but also an important moleculesagainst oxidative stress. ALDH2reduced the cytotoxicity of acetaldehyde andother aliphatic aldehydes and played an antioxidant effect, having a protectiveeffect on the heart.
The ALDH2was encoded by ALDH2gene. Domestic and internationalstudies showed that the ALDH2gene involved in the occurrence anddevelopment of coronary heart disease. The ALDH2gene showed singlenucleotide polymorphism. The most studied genetic polymorphism was theGlu504Lys polymorphism locus (as known as rs671). This locus occurrednucleotide substitution, guanine (G, wild-type) was replaced by adenine (A,mutant). ALDH2polymorphism had two alleles: wild-type with the catalyticactivity was called the G allele (ALDH2*1), and the mutant with catalyticability inactivation was called the A allele (ALDH2*2). So this locus had threegenotypes, wild homozygote (GG as known as ALDH2*1/*1), mutationheterozygous (GA as known as ALDH2*1/*2) and mutation homozygote (AAas known as ALDH2*2/*2). Japanese researchers found that the ALDH2mutation genotype was the independent risk factor of myocardial infarction(MI) in Japanese men.
Nitrates was a drug having an earlier and common application in the fieldof cardiovascular disease, but the mechanism of nitrates biotransformation was not yet fully clarified. Recently, researchers realized that ALDH2mayplay an important role in the clinical efficacy of nitroglycerin. However, thestudy on ALDH2different genotype and nitrates especially isosorbidemononitrate clinical efficacy in angina patients was few.
This study was designed to explore the association between aldehydedehydrogenase2activity levels and aldehyde dehydrogenase2genotype withcoronary heart disease, especially myocardial infarction, and the relationshipbetween ALDH2genotype and nitroglycerin and isosorbide mononitrateclinical efficacy in angina patients, providing the theoretical basis and newideas for the clinical assessment, pathogenesis and drug treatment of coronaryheart disease.
Part1Association study between aldehyde dehydrogenase2activity levelsand coronary heart disease
Objective: To investigate the relationship between the aldehydedehydrogenase2activity levels and coronary heart disease.
Methods: A total of191subjects hospitalized in our hospital fromJanuary2011to December2012were enrolled, including62cases of patientswith angina pectoris,64cases of acute myocardial infarction (AMI), and65cases in the control group. The clinical basic data were recorded, includingage, sex, history of smoking, drinking, hypertension and diabetes，the patients'height, weight, and BMI (body mass index, BMI). The blood samples of allthe selected subjects were collected in the next day morning. Activity level ofALDH2was tested by blood ALDH2activity colorimetric quantitativedetection kit, and the levels of total cholesterol (TC), triglycerides (TG),high-density lipoprotein cholesterol (HDL-C) and low-density lipoproteincholesterol (LDL-C) were tested by enzymatic determination. SPSS16.0statistics software was used to compare the clinical data, ALDH2activity level,and the correlation between the plasma ALDH2activity level and BMI, TC,TG, HDL-C and LDL-C levels in the three groups of patients.
Results:
（1）The ALDH2activity level of the control group, angina group and AMI group declined in turn[(23.76±6.31) U/L,(22.37±6.03) U/L, and(21.14±5.76) U/L, respectively], but the difference was not statisticallysignificant (p＞0.05).
（2）Correlation analysis showed that the level of ALDH2was notrelated to BMI, TC, TG, HDL-C and LDL-C in control group, angina groupand AMI group (p＞0.05).
Conclusions: The ALDH2activity in control group, angina group andAMI group had a trend of descend, but the difference was not statisticallysignificant. ALDH2activity level was not related to the level of BMI, TC, TG,HDL-C and LDL-C. This suggested that ALDH2activity level had nothing todo with the severity of coronary heart disease, and ALDH2activity was not apredict indicators to judge the severity of coronary heart disease.
Part2Association study between aldehyde dehydrogenase2genotype andacute myocardial infarction
Objective: To explore the correlation between aldehyde dehydrogenase2genotype and acute myocardial infarction.
Methods: A total of431subjects hospitalized in our hospital fromJanuary2011to December2012were selected for the research, including210cases of acute myocardial infarction (AMI) patients and221cases in thecontrol. The clinical basic data were recorded, including age, sex, history ofsmoking，drinking, hypertension and diabetes, the patients' height, weight, andBMI. The levels of total cholesterol (TC), triglycerides (TG), high-densitylipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol(LDL-C) were tested by enzymatic determination. The blood samples of allthe selected subjects were collected for the extraction of genomic DNA, andthe Glu504Lys locus of ALDH2gene was detected by direct sequencing. Allthe patients were underwent coronal artery angiography. According to thelesion involved the count, it was divided into single vessel lesion, doublevessel lesion and triple lesion. SPSS16.0data statistics software was used tocompare the basic clinical data, the genotype and allele frequencies of the twogroups, and the stratified analysis was carried out according to the drinking and the age of the study population. Multivariate Logistic regression analysiswas used to determine the risk factor of the disease, and the odds ratio (OR)and95%confidence intervals (95%CI) were calculated.
Results:
（1）The distribution of ALDH2genotype in AMI group and controlgroup was in Hardy-Weinberg equilibrium.
（2）The genotype frequencies of GG, GA and AA in AMI group were asfollows:50.48%,43.81%,5.71%, and the control group were:69.68%,28.05%,2.26%. The distributional difference of three genotypes in the twogroups was statistically significant (p＜0.001). The G allele frequency in AMIgroup was lower than that in control group (72.38%vs.83.71%), and the Aallele frequency in AMI group was higher than that in control group (27.62%vs.16.29%). The difference was statistically significant (p＜0.05).
（3）Taking the presence or absence of AMI as the dependent variable,age, gender, history of smoking, drinking, hypertension and diabetes, BMI,TC, TG, HDL-C, LDL-C, and ALDH2genotype were introduced to Logisticregression model, multi-factor Logistic regression analysis showed thatALDH2GA+AA mutant genotype was the risk factor of AMI (OR=1.300,95%CI:1.035-1.634, p=0.0243).
（4）ALDH2genotype had no significant correlation with the coronarylesion count in AMI group (p＞0.05).
（5）Stratified analysis were carried out according to the drinking ofstudy population, multi-factor Logistic regression analysis showed thatGA+AA mutant genotype was the risk factor of AMI in the non-drinkingcrowd (OR=1.791,95%CI:1.005-3.189, p=0.048); while GA+AA mutantgenotype was not the risk factor of AMI in the drinking crowd (OR=1.041,95%CI:0.974-1.113, p=0.2327).
（6）Stratified analysis were carried out according to the age of studypopulation, multi-factor Logistic regression analysisis did not found GA+AAmutant genotype increase the risk of AMI in early-onset crowd (man＜55years old, women＜65years old)（OR=1.030,95%CI:0.983-1.079, p=0.2097），suggesting that ALDH2GA+AA mutant genotype was not the riskfactor of premature AMI; while in late-onset crowd (men≥55years old,women≥65years old) multi-factor Logistic regression analysisis found theindividuals carrying GA+AA mutant genotype had high risk of AMI(OR=1.424,95%CI:1.029-1.969, p=0.0329).
Conclusions:
（1）ALDH2GA+AA mutant genotype was the independent risk factorof AMI.
（2）ALDH2genotype had no significant correlation with the coronarylesion count in AMI patients.
（3）ALDH2GA+AA mutant genotype was the risk factor of AMI innon-drinking crowd, but not in drinking crowd. ALDH2GG+AA mutantgenotype was the risk factor of late-onset AMI, but not the risk factor ofearly-onset AMI.
Part3Correlation study of the aldehyde dehydrogenase2differentgenotype and the clinical efficacy in angina pectoris patients withapplication of nitroglycerin and isosorbide mononitrate.
Objective: To explore the relationship between aldehyde dehydrogenase2different genotype and the clinical efficacy in angina pectoris patients withapplication of nitroglycerin and isosorbide mononitrate.
Methods:395patients with angina pectoris hospitalized in our hospitalfrom January2011to December2012were selected for the research. Thepatients were randomly divided into2groups,201cases of nitroglyceringroup,194cases of isosorbide mononitrate group. The clinical basic data wererecorded, including age, sex, history of smoking，drinking, hypertension anddiabetes, the patients' height, weight, and BMI. The levels of total cholesterol(TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) andlow-density lipoprotein cholesterol (LDL-C) were tested by enzymaticdetermination. The blood samples of all the selected subjects were collectedfor the extraction of genomic DNA, and the Glu504Lys locus of ALDH2genewas detected by direct sequencing. Electrocardiogram (ECG) and liver and kidney function were observed in the subjects during the treatment. Theangina attack frequency, magnitude, duration and the changes of resting ECGST-T were observed in different genotype patients and the adverse reactionsduring the treatment were also recorded. The clinical symptom and ECGefficacy were compared in the patients.
Results:
（1）The ALDH2genotype distribution in nitroglycerin group andisosorbide mononitrate group was no significant difference (p＞0.05).
（2）Clinical symptom efficacy of nitroglycerin treatment: extremelyeffective40cases, effective55cases, ineffective40cases in ALDH2GG wildgenotype; extremely effective17cases, effective20cases, ineffective29casesin ALDH2GA+AA mutant genotype; the clinical symptom efficacy has nosignificant difference between ALDH2GG wild genotype and GA+AAmutant genotype patients with nitroglycerin treatment (p＞0.05).
ECG efficacy of nitroglycerin treatment: extremely effective28cases,effective56cases, ineffective51cases in ALDH2GG wild genotype;extremely effective10cases, effective21cases, ineffective35cases inALDH2GA+AA mutant genotype; the ECG efficacy has no significantdifference between ALDH2GG wild genotype and GA+AA mutant genotypepatients with nitroglycerin treatment (p＞0.05).
（3）Clinical symptom efficacy of isosorbide mononitrate treatment:extremely effective47cases, effective73cases, ineffective12cases inALDH2GG wild genotype; extremely effective20cases, effective31cases,ineffective11cases in ALDH2GA+AA mutant genotype; the clinicalsymptom efficacy has no significant difference between ALDH2GG wildgenotype and GA+AA mutant genotype patients with isosorbide mononitratetreatment (p＞0.05).
ECG efficacy of isosorbide mononitrate treatment: extremely effective41cases, effective67cases, ineffective24cases in ALDH2GG wild genotype;extremely effective18cases, effective26cases, ineffective18cases inALDH2GA+AA mutant genotype; the ECG efficacy has no significant difference between ALDH2GG wild genotype and GA+AA mutant genotypepatients with isosorbide mononitrate treatment treatment (p＞0.05).
（4）The clinical symptom efficacy and ECG efficacy of ALDH2GGwild genotype patients with nitroglycerin were better than those withisosorbide mononitrate treatment and the difference was statisticallysignificant (p＜0.05). The clinical symptom efficacy and ECG efficacy ofALDH2GA+AA mutant genotype patients with nitroglycerin were better thanthose with isosorbide mononitrate treatment and the difference wasstatistically significant (p＜0.05),
Conclusions:
（1）The clinical symptom efficacy and ECG efficacy has no significantdifference between ALDH2GG wild genotype and GA+AA mutant genotypeangina patients with nitroglycerin treatment.
（2）The clinical symptom efficacy and ECG efficacy has no significantdifference between ALDH2GG wild genotype and GA+AA mutant genotypeangina patients with isosorbide mononitrate treatment.
（3）Whether ALDH2GG wild genotype or GA+AA mutant genotypeangina patients, the application of isosorbide mononitrate had more betterclinical efficacy, less adverse and higher safety than nitroglycerin.
ALDH2由ALDH2基因编码，有学者认为ALDH2基因参与了冠心病的发生与发展。ALDH2基因具有单核苷酸多态性，其中研究最多的是Glu504Lys多态性位点（又称rs671），该位点发生碱基置换，即鸟嘌呤（G，野生型）被腺嘌呤（A，突变型）替代。所以，ALDH2有两个等位基因：G等位基因（ALDH2*1）和A等位基因（ALDH2*2），导致人群中该酶基因型有3种情况：野生纯合型（GG型又称ALDH2*1/*1）、突变杂合型（GA型又称ALDH2*1/*2）和突变纯合型（AA型又称ALDH2*2/*2）。日本学者发现ALDH2突变基因型是日本男性心肌梗死（myocardial infarction，MI）的独立危险因素。
硝酸酯类药物是心血管领域中应用较早且应用较广泛的药物，但是硝酸酯类药物的生物转化机制仍未被完全阐明。最近，研究人员发现ALDH2对硝酸甘油发挥临床疗效具有一定影响，但是关于ALDH2不同基因型患者与硝酸酯类药物尤其是单硝酸异山梨酯治疗心绞痛临床疗效之间的研究相对较少。
本研究拟从ALDH2活性水平及基因型方面，探讨ALDH2与冠心病特别是心肌梗死的相关性，以及ALDH2不同基因型患者临床应用硝酸甘油和单硝酸异山梨酯有效性之间的关系，为冠心病临床评估、发病机制以及药物治疗提供一定的理论依据和新的思路。
第一部分乙醛脱氢酶2活性水平与冠心病的相关性研究
目的：探讨乙醛脱氢酶2活性水平与冠心病之间的关系。
方法：选择2011年1月至2012年12月在唐山工人医院心内科住院的患者共191例，其中心绞痛患者62例，急性心肌梗死（acute myocardialinfarction，AMI）患者64例，对照者65例。记录所有研究对象临床基本资料，包括：年龄、性别、吸烟史、饮酒史、高血压病史和糖尿病病史，测量受试对象身高（Height，H）、体重（Weight，W），计算体重指数（body mass index，BMI）。入选研究对象于入院第二天清晨采集外周静脉血，采用血液ALDH2活性比色法定量检测试剂盒检测ALDH2活性水平；同时采用酶法测定总胆固醇（total cholesterol，TC）、甘油三酯（triglycerides，TG）、高密度脂蛋白胆固醇（high density lipoproteincholesterol，HDL-C）和低密度脂蛋白胆固醇（low density lipoproteincholesterol，LDL-C）。采用SPSS16.0软件进行数据统计，对三组患者临床基本资料、ALDH2活性水平进行比较，采用相关分析分析血浆ALDH2活性水平与BMI、TC、TG、HDL-C、LDL-C水平的相关性。
结果：
（1）对照组、心绞痛组、AMI组ALDH2活性水平分别为（23.76±6.31）U/L、（22.37±6.03）U/L、（21.14±5.76）U/L，三组活性水平依次降低，但差异无统计学意义（p＞0.05）。
（2）相关分析显示对照组、心绞痛组、AMI组ALDH2水平与BMI、TC、TG、HDL-C、LDL-C水平均无相关性（p＞0.05）。
结论：对照组、心绞痛组和AMI组ALDH2活性水平依次下降，但差异无统计学意义，ALDH2水平与BMI、TC、TG、HDL-C、LDL-C水平无相关性，提示ALDH2活性水平与冠心病病情严重程度无关，ALDH2不能作为判断冠心病病情严重程度的预测指标。
第二部分乙醛脱氢酶2基因型与急性心肌梗死的相关性研究
目的：探讨乙醛脱氢酶2基因型与急性心肌梗死之间的相关性。
方法：选择2011年1月至2012年12月在唐山工人医院心内科住院诊断为急性心肌梗死（AMI）患者210例和对照者221例。记录所有研究对象临床基本资料，包括：年龄、性别、吸烟史、饮酒史、高血压病史和糖尿病病史，测量受试对象身高（H）、体重（W），计算体重指数（BMI）。采用酶法测定总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）。采集所有受试者外周静脉血提取基因组DNA，采用测序方法检测ALDH2基因Glu504Lys位点多态性。所有入选患者均进行冠状动脉造影检查，根据病变累及支数，分为单支病变、双支病变和三支病变。采用SPSS16.0软件进行数据统计，对AMI组和对照组临床基本资料、基因型频率和等位基因频率进行比较，并进一步对研究人群的饮酒情况和年龄情况进行分层分析，采用多因素Logistic回归分析判断疾病危险因素作用的大小，计算比数比（Odds Ratio，OR）和95%可信区间（95%Confidence Index，95%CI）。
结果：
（1）AMI组和对照组ALDH2基因型分布均符合Hardy-Weinberg平衡。
（2）AMI组GG、GA、AA基因型频率分别为：50.48%、43.81%、5.71%，对照组GG、GA、AA基因型频率分别为：69.68%、28.05%、2.26%，两组基因型分布差异有统计学意义（p＜0.001）。AMI组G等位基因频率低于对照组（72.38%vs.83.71%），A等位基因频率高于对照组（27.62%vs.16.29%），两组比较差异有统计学意义（p＜0.05）。
（3）以有无AMI为因变量，将年龄、性别、吸烟史、饮酒史、高血压病史、糖尿病病史、BMI、TC、TG、HDL-C、LDL-C、ALDH2基因型引入Logistic回归模型，多因素Logistic回归分析显示ALDH2GA+AA突变基因型是AMI的危险因素（OR=1.300，95%CI：1.035-1.634，p=0.0243）。
（4）AMI组ALDH2不同基因型与冠状动脉病变支数无明显相关性（p＞0.05）。
（5）根据研究人群的饮酒情况进行分层分析，在非饮酒人群中多因素Logistic回归分析显示，GA+AA突变基因型是AMI的危险因素（OR=1.791，95%CI：1.005-3.189，p=0.048）；在饮酒人群中Logistic回归分析显示，GA+AA突变基因型不是AMI的危险因素（OR=1.041，95%CI：0.974-1.113，p=0.2327）。
（6）根据研究人群的年龄进行分层分析，多因素Logistic回归分析显示，在早发人群（男性＜55岁，女性＜65岁）中未发现携带GA+AA突变基因型个体患AMI的风险增加（OR=1.030，95%CI：0.983-1.079，p=0.2097），提示ALDH2GA+AA突变基因型不是早发AMI的危险因素；在晚发人群（男性≥55岁，女性≥65岁）中发现携带GA+AA突变基因型个体患AMI的风险增加（OR=1.424，95%CI:1.029-1.969，p=0.0329）。
结论：
（1）ALDH2GA+AA突变基因型是AMI的危险因素。
（2）AMI患者ALDH2基因型与冠状动脉病变支数无相关性。
（3）分层分析显示，ALDH2GA+AA突变基因型是非饮酒人群AMI的危险因素，而不是饮酒人群AMI的危险因素；ALDH2GA+AA突变基因型是晚发AMI的危险因素，而不是早发AMI的危险因素。
第三部分乙醛脱氢酶2不同基因型心绞痛患者应用硝酸甘油和单硝酸异山梨酯临床疗效的相关性研究
目的：探讨乙醛脱氢酶2不同基因型心绞痛患者应用硝酸甘油和单硝酸异山梨酯临床疗效之间的关系。
方法：选择2011年1月至2012年12月在唐山工人医院心内科住院诊断为冠心病心绞痛患者395例，将患者随机分为2组，硝酸甘油组201例，单硝酸异山梨酯组194例，记录所有研究对象临床基本资料，包括：年龄、性别、吸烟史、饮酒史、高血压病史和糖尿病病史等，测量受试对象身高（H）、体重（W），计算体重指数（BMI）。采用酶法测定总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）。采集所有受试者外周静脉血提取基因组DNA，采用测序方法检测ALDH2基因Glu504Lys位点多态性。所有研究对象用药期间，定期做心电图及肝肾功能检查，观察两组内不同基因型患者心绞痛发作频率、程度、持续时间，对比静息心电图ST-T变化，并记录用药期间不良反应的发生情况，比较不同患者的临床症状疗效和心电图疗效。
结果：
（1）硝酸甘油组和单硝酸异山梨酯组ALDH2基因型分布无明显差异（p＞0.05）。
（2）应用硝酸甘油的临床症状疗效：ALDH2GG野生基因型患者显效40例，有效55例，无效40例；ALDH2GA+AA突变基因型患者显效17例，有效20例，无效29例。GG野生基因型患者、GA+AA突变基因型患者应用硝酸甘油的临床症状疗效差异无统计学意义（p＞0.05）。
应用硝酸甘油的心电图疗效：ALDH2GG野生基因型患者显效28例，有效56例，无效51例；ALDH2GA+AA突变基因型患者显效10例，有效21例，无效35例。GG野生基因型患者、GA+AA突变基因型患者应用硝酸甘油的心电图疗效差异无统计学意义（p＞0.05）。
（3）应用单硝酸异山梨酯的临床症状疗效：ALDH2GG野生基因型患者显效47例，有效73例，无效12例；ALDH2GA+AA突变基因型患者显效20例，有效31例，无效11例。GG野生基因型患者、GA+AA突变基因型患者应用单硝酸异山梨酯的临床症状疗效差异无统计学意义（p＞0.05）。
应用单硝酸异山梨酯的心电图疗效：ALDH2GG野生基因型患者显效41例，有效67例，无效24例；ALDH2GA+AA突变基因型患者显效18例，有效26例，无效18例。GG野生基因型患者、GA+AA突变基因型患者应用单硝酸异山梨酯的心电图疗效差异无统计学意义（p＞0.05）。
（4）ALDH2GG野生基因型患者应用单硝酸异山梨酯治疗心绞痛的临床症状疗效、心电图疗效优于硝酸甘油，差异有统计学意义（p＜0.05）；ALDH2GA+AA突变基因型患者应用单硝酸异山梨酯治疗心绞痛的临床症状疗效、心电图疗效也优于硝酸甘油，差异有统计学意义，（p＜0.05）。
结论：
（1）ALDH2GG野生基因型患者与GA+AA突变基因型患者应用硝酸甘油治疗心绞痛的临床疗效无差异。
（2）ALDH2GG野生基因型患者与GA+AA突变基因型患者应用单硝酸异山梨酯治疗心绞痛的临床疗效无差异。
（3）无论是ALDH2GG野生基因型患者还是GA+AA突变基因型患者，应用单硝酸异山梨酯治疗心绞痛的临床疗效均优于硝酸甘油，且不良反应小，安全性高。
Coronary atherosclerotic heart disease (CAD) refered to coronaryatherosclerosis caused vascular stenosis or obstruction, leading to myocardialischemia, hypoxia, together with coronary functional change (spasm) werecalled coronary heart disease (CHD). CHD was a common disease having aserious threat to health, affecting the quality of life. Currently, studies haveshown that aldehyde dehydrogenase2(ALDH2) was not only one of the keyenzyme in the process of alcohol metabolism, but also an important moleculesagainst oxidative stress. ALDH2reduced the cytotoxicity of acetaldehyde andother aliphatic aldehydes and played an antioxidant effect, having a protectiveeffect on the heart.
The ALDH2was encoded by ALDH2gene. Domestic and internationalstudies showed that the ALDH2gene involved in the occurrence anddevelopment of coronary heart disease. The ALDH2gene showed singlenucleotide polymorphism. The most studied genetic polymorphism was theGlu504Lys polymorphism locus (as known as rs671). This locus occurrednucleotide substitution, guanine (G, wild-type) was replaced by adenine (A,mutant). ALDH2polymorphism had two alleles: wild-type with the catalyticactivity was called the G allele (ALDH2*1), and the mutant with catalyticability inactivation was called the A allele (ALDH2*2). So this locus had threegenotypes, wild homozygote (GG as known as ALDH2*1/*1), mutationheterozygous (GA as known as ALDH2*1/*2) and mutation homozygote (AAas known as ALDH2*2/*2). Japanese researchers found that the ALDH2mutation genotype was the independent risk factor of myocardial infarction(MI) in Japanese men.
Nitrates was a drug having an earlier and common application in the fieldof cardiovascular disease, but the mechanism of nitrates biotransformation was not yet fully clarified. Recently, researchers realized that ALDH2mayplay an important role in the clinical efficacy of nitroglycerin. However, thestudy on ALDH2different genotype and nitrates especially isosorbidemononitrate clinical efficacy in angina patients was few.
This study was designed to explore the association between aldehydedehydrogenase2activity levels and aldehyde dehydrogenase2genotype withcoronary heart disease, especially myocardial infarction, and the relationshipbetween ALDH2genotype and nitroglycerin and isosorbide mononitrateclinical efficacy in angina patients, providing the theoretical basis and newideas for the clinical assessment, pathogenesis and drug treatment of coronaryheart disease.
Part1Association study between aldehyde dehydrogenase2activity levelsand coronary heart disease
Objective: To investigate the relationship between the aldehydedehydrogenase2activity levels and coronary heart disease.
Methods: A total of191subjects hospitalized in our hospital fromJanuary2011to December2012were enrolled, including62cases of patientswith angina pectoris,64cases of acute myocardial infarction (AMI), and65cases in the control group. The clinical basic data were recorded, includingage, sex, history of smoking, drinking, hypertension and diabetes，the patients'height, weight, and BMI (body mass index, BMI). The blood samples of allthe selected subjects were collected in the next day morning. Activity level ofALDH2was tested by blood ALDH2activity colorimetric quantitativedetection kit, and the levels of total cholesterol (TC), triglycerides (TG),high-density lipoprotein cholesterol (HDL-C) and low-density lipoproteincholesterol (LDL-C) were tested by enzymatic determination. SPSS16.0statistics software was used to compare the clinical data, ALDH2activity level,and the correlation between the plasma ALDH2activity level and BMI, TC,TG, HDL-C and LDL-C levels in the three groups of patients.
Results:
（1）The ALDH2activity level of the control group, angina group and AMI group declined in turn[(23.76±6.31) U/L,(22.37±6.03) U/L, and(21.14±5.76) U/L, respectively], but the difference was not statisticallysignificant (p＞0.05).
（2）Correlation analysis showed that the level of ALDH2was notrelated to BMI, TC, TG, HDL-C and LDL-C in control group, angina groupand AMI group (p＞0.05).
Conclusions: The ALDH2activity in control group, angina group andAMI group had a trend of descend, but the difference was not statisticallysignificant. ALDH2activity level was not related to the level of BMI, TC, TG,HDL-C and LDL-C. This suggested that ALDH2activity level had nothing todo with the severity of coronary heart disease, and ALDH2activity was not apredict indicators to judge the severity of coronary heart disease.
Part2Association study between aldehyde dehydrogenase2genotype andacute myocardial infarction
Objective: To explore the correlation between aldehyde dehydrogenase2genotype and acute myocardial infarction.
Methods: A total of431subjects hospitalized in our hospital fromJanuary2011to December2012were selected for the research, including210cases of acute myocardial infarction (AMI) patients and221cases in thecontrol. The clinical basic data were recorded, including age, sex, history ofsmoking，drinking, hypertension and diabetes, the patients' height, weight, andBMI. The levels of total cholesterol (TC), triglycerides (TG), high-densitylipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol(LDL-C) were tested by enzymatic determination. The blood samples of allthe selected subjects were collected for the extraction of genomic DNA, andthe Glu504Lys locus of ALDH2gene was detected by direct sequencing. Allthe patients were underwent coronal artery angiography. According to thelesion involved the count, it was divided into single vessel lesion, doublevessel lesion and triple lesion. SPSS16.0data statistics software was used tocompare the basic clinical data, the genotype and allele frequencies of the twogroups, and the stratified analysis was carried out according to the drinking and the age of the study population. Multivariate Logistic regression analysiswas used to determine the risk factor of the disease, and the odds ratio (OR)and95%confidence intervals (95%CI) were calculated.
Results:
（1）The distribution of ALDH2genotype in AMI group and controlgroup was in Hardy-Weinberg equilibrium.
（2）The genotype frequencies of GG, GA and AA in AMI group were asfollows:50.48%,43.81%,5.71%, and the control group were:69.68%,28.05%,2.26%. The distributional difference of three genotypes in the twogroups was statistically significant (p＜0.001). The G allele frequency in AMIgroup was lower than that in control group (72.38%vs.83.71%), and the Aallele frequency in AMI group was higher than that in control group (27.62%vs.16.29%). The difference was statistically significant (p＜0.05).
（3）Taking the presence or absence of AMI as the dependent variable,age, gender, history of smoking, drinking, hypertension and diabetes, BMI,TC, TG, HDL-C, LDL-C, and ALDH2genotype were introduced to Logisticregression model, multi-factor Logistic regression analysis showed thatALDH2GA+AA mutant genotype was the risk factor of AMI (OR=1.300,95%CI:1.035-1.634, p=0.0243).
（4）ALDH2genotype had no significant correlation with the coronarylesion count in AMI group (p＞0.05).
（5）Stratified analysis were carried out according to the drinking ofstudy population, multi-factor Logistic regression analysis showed thatGA+AA mutant genotype was the risk factor of AMI in the non-drinkingcrowd (OR=1.791,95%CI:1.005-3.189, p=0.048); while GA+AA mutantgenotype was not the risk factor of AMI in the drinking crowd (OR=1.041,95%CI:0.974-1.113, p=0.2327).
（6）Stratified analysis were carried out according to the age of studypopulation, multi-factor Logistic regression analysisis did not found GA+AAmutant genotype increase the risk of AMI in early-onset crowd (man＜55years old, women＜65years old)（OR=1.030,95%CI:0.983-1.079, p=0.2097），suggesting that ALDH2GA+AA mutant genotype was not the riskfactor of premature AMI; while in late-onset crowd (men≥55years old,women≥65years old) multi-factor Logistic regression analysisis found theindividuals carrying GA+AA mutant genotype had high risk of AMI(OR=1.424,95%CI:1.029-1.969, p=0.0329).
Conclusions:
（1）ALDH2GA+AA mutant genotype was the independent risk factorof AMI.
（2）ALDH2genotype had no significant correlation with the coronarylesion count in AMI patients.
（3）ALDH2GA+AA mutant genotype was the risk factor of AMI innon-drinking crowd, but not in drinking crowd. ALDH2GG+AA mutantgenotype was the risk factor of late-onset AMI, but not the risk factor ofearly-onset AMI.
Part3Correlation study of the aldehyde dehydrogenase2differentgenotype and the clinical efficacy in angina pectoris patients withapplication of nitroglycerin and isosorbide mononitrate.
Objective: To explore the relationship between aldehyde dehydrogenase2different genotype and the clinical efficacy in angina pectoris patients withapplication of nitroglycerin and isosorbide mononitrate.
Methods:395patients with angina pectoris hospitalized in our hospitalfrom January2011to December2012were selected for the research. Thepatients were randomly divided into2groups,201cases of nitroglyceringroup,194cases of isosorbide mononitrate group. The clinical basic data wererecorded, including age, sex, history of smoking，drinking, hypertension anddiabetes, the patients' height, weight, and BMI. The levels of total cholesterol(TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) andlow-density lipoprotein cholesterol (LDL-C) were tested by enzymaticdetermination. The blood samples of all the selected subjects were collectedfor the extraction of genomic DNA, and the Glu504Lys locus of ALDH2genewas detected by direct sequencing. Electrocardiogram (ECG) and liver and kidney function were observed in the subjects during the treatment. Theangina attack frequency, magnitude, duration and the changes of resting ECGST-T were observed in different genotype patients and the adverse reactionsduring the treatment were also recorded. The clinical symptom and ECGefficacy were compared in the patients.
Results:
（1）The ALDH2genotype distribution in nitroglycerin group andisosorbide mononitrate group was no significant difference (p＞0.05).
（2）Clinical symptom efficacy of nitroglycerin treatment: extremelyeffective40cases, effective55cases, ineffective40cases in ALDH2GG wildgenotype; extremely effective17cases, effective20cases, ineffective29casesin ALDH2GA+AA mutant genotype; the clinical symptom efficacy has nosignificant difference between ALDH2GG wild genotype and GA+AAmutant genotype patients with nitroglycerin treatment (p＞0.05).
ECG efficacy of nitroglycerin treatment: extremely effective28cases,effective56cases, ineffective51cases in ALDH2GG wild genotype;extremely effective10cases, effective21cases, ineffective35cases inALDH2GA+AA mutant genotype; the ECG efficacy has no significantdifference between ALDH2GG wild genotype and GA+AA mutant genotypepatients with nitroglycerin treatment (p＞0.05).
（3）Clinical symptom efficacy of isosorbide mononitrate treatment:extremely effective47cases, effective73cases, ineffective12cases inALDH2GG wild genotype; extremely effective20cases, effective31cases,ineffective11cases in ALDH2GA+AA mutant genotype; the clinicalsymptom efficacy has no significant difference between ALDH2GG wildgenotype and GA+AA mutant genotype patients with isosorbide mononitratetreatment (p＞0.05).
ECG efficacy of isosorbide mononitrate treatment: extremely effective41cases, effective67cases, ineffective24cases in ALDH2GG wild genotype;extremely effective18cases, effective26cases, ineffective18cases inALDH2GA+AA mutant genotype; the ECG efficacy has no significant difference between ALDH2GG wild genotype and GA+AA mutant genotypepatients with isosorbide mononitrate treatment treatment (p＞0.05).
（4）The clinical symptom efficacy and ECG efficacy of ALDH2GGwild genotype patients with nitroglycerin were better than those withisosorbide mononitrate treatment and the difference was statisticallysignificant (p＜0.05). The clinical symptom efficacy and ECG efficacy ofALDH2GA+AA mutant genotype patients with nitroglycerin were better thanthose with isosorbide mononitrate treatment and the difference wasstatistically significant (p＜0.05),
Conclusions:
（1）The clinical symptom efficacy and ECG efficacy has no significantdifference between ALDH2GG wild genotype and GA+AA mutant genotypeangina patients with nitroglycerin treatment.
（2）The clinical symptom efficacy and ECG efficacy has no significantdifference between ALDH2GG wild genotype and GA+AA mutant genotypeangina patients with isosorbide mononitrate treatment.
（3）Whether ALDH2GG wild genotype or GA+AA mutant genotypeangina patients, the application of isosorbide mononitrate had more betterclinical efficacy, less adverse and higher safety than nitroglycerin.
引文
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