Association Of Aldehyde Dehydrogenase2Activity Levels And Genotype With Coronary Heart Disease

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 diseaseObjective: 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 infarctionObjective: 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.