| Every year,about 18.0 million people in the world will die from cardiovascular diseases,accounting for 31%of the total global deaths.This phenomenon is particularly prominent in China,where cardiovascular disease deaths account for more than 40%of all the deaths of Chinese residents.Cardiovascular death prevalence and fatality rates are still on the increase.In the world yearly,about 9.4 million people die of high blood pressure(Essential Hypertension,EH),which is one of the three major risk factors of the global burden of disease.High blood pressure,ischemic heart disease and stroke have clearly become the most important risk factors for cardiovascular disease occurrence and development in China.More serious is that the prevalence of cardiovascular disease tends to increase year by year,gradually increasing in the younger population.According to"Chinese Cardiovascular Disease Report 2017",270 million is the number of patients with high blood pressure in China,while the global number is more than 1.1 billion hypertension patients.Hypertension preva-lence rate is about 20%,with the number of hypertension patients speeding up the rising trend.High blood pressure is becoming more and more the important risk factor of cardiovascular diseases.Blood pressure is affected dynamically by individual activities,postures,mental stress and drugs.Because the genetic characteristics of hypertension patients showed relative stability;it is speculated that explore the monitoring of the genotype of hypertension patients and the correlation between hypertension and cardiovascular events.Aldosterone,as an important halocorticoid hormone in the human body,is secreted by spheroid adrenal cortical cells and acts on the halocorticoid receptor(MR).Increased aldosterone levels will significantly increase the risks of hypertension and hypertension related target organ damage.Aldosterone synthase is encoded by the aldosterone synthase gene-cytochrome P(CYP)CYP11B2.It is a catalytic enzyme that regulates the final biochemical reaction of aldosterone synthesis by adrenal cortical globular cells.The aldosterone synthase gene plays an important role in aldosterone biosynthesis.Relevant studies have confirmed that the polymorphism of aldosterone synthase gene can promote the occurrence of cardiovascular disease in the general population.Researchers could not explain whether the correlation between the polymorphism and cardiovascular disease also existed in patients with hypertension.In addition,allelic frequency disease was different among different ethnic groups,but the results could not be applied to the Chinese population.In this study the Chinese patients with high blood pressure were used as the research objects,studying the CYP11B2 gene.Chinese patients with high blood pressure of each genotype and allele frequency were compared with high blood pressure patients of other countries.The difference of genotype and allele frequency were explored.At the same time the CYP11B2 gene polymorphisms and hypertension patients in China were evaluated,as the relationship between the cardiovascular events were further discussed.Polymorphisms,aldosterone synthase gene and senile primary hypertension patients with left ventricular hypertrophy were correlated for Chinese patients with high blood pressure in clinical treatment.This correlation was to reduce the occurrence of cardiovascular events and provide theoretical basis and guiding significance.Part One Association of-344C/T polymorphism in the aldosterone synt-hase(CYP11B2)gene with cardiac and cerebrovascular events in Chinese patients with hypertensionObjective:The-344C/T polymorphism of CYP11B2 gene is inconsistent with the conclusions obtained from studies on the occurrence of essential hypertension cardiovascular and cerebrovascular events.The-344C/T allele frequency and the incidence of cardiovascular disease are ethnically different in healthy individuals,so these findings may not be applicable to the Chinese population.Furthermore,most studies have been conducted in healthy populations and cannot prove,at least to a certain extent,a genetic association in hypertension.Therefore,whether the-344C/T allele affects the incidence of cardiovascular disease in patients with hypertension needs to be confirmed in a cohort based study on hypertension.Therefore,whether the-344C allele affects the incidence of cardiovascular disease in Chinese patients with hypertension remains unclear and needs to be explored.Methods:In this study,820 patients diagnosed with hypertension in the outpatient department were recruited from Hebei Provincial People's Hospital and Beijing Xuanwu Hospital from June,2004 to May,2006.The following clinical investigations were carried out:(1)CYP11B2 genotyping of all patients was detected by Taq Man-Realtime PCR;(2)All subjects were followed up for 11 years to record major adverse cardiovascular events(MACEs),including stroke,coronary artery disease(CAD),and coronary artery disease death;(3)The established multivariate Cox analysis adjusted for cardiovascular risk factors was adopted and SPSS17.0 was used for statistical analysis.Results:1.General clinical data of the subjects:A total of 820 hypertensive patients were included in this study,of whom 65 hypertensive patients were excluded due to lack of follow-up.Among the remaining 755 EH patients,399were males and 356 were females,aged 60.52±12.61 years.2.Genotyping results of CYP11B2:T allele homozygous(TT genotype)in 282 cases(37.4%):There were 361 heterozygous(CT genotype)cases(47.8%)and 112 homozygous(CC genotype)cases(14.8%).There was no significant difference in age and sex ratio among all groups.There was no further significant correlation with CYP11B2 genotype.3.The incidence of cardiovascular events:After a mean follow-up of7.60±1.12 years,the incidence of MACEs was significantly higher in CYP11B2 CC genotypes than in CT and TT genotypes.4.Risk factor risk assessment:The CC variant of CYP11B2 gene was a significant and independent predictor of MACEs(HR=2.049)and CAD and stroke.Summary:The CYP11B2-344 CC genotype is a risk factor for coronary heart disease and stroke in patients with hypertension.It is independent of other existing cardiovascular risk factors in Chinese patients with hypertension and can be used as a risk predictor for cardiovascular events in patients with hypertension.However,the mechanism of this genotype variation needs further study.Part Two Relationship between CYPl l B2 gene polymorphism and leftventricular hypertrophy in elderly essential hypertension pa-tientsObjective:In this part,the correlation analysis of C-344T site of CYP11B2 gene and elderly patients with essential hypertension complicated with LVH was conducted to explore the relationship between this locus variant genotype and LVH The correlation analysis was to provide the theoretical basis for the diagnosis and treatment of Chinese patients with essential hypertension complicated with LVH.Methods:Selected in cardiology:Hebei Provincial People's Hospital and Beijing Xuanwu Hospital confirmed 434 cases of patients with senile primary hypertension and asked for details of all the patients'medical history:physical examination with completion of all the relevant checks(blood pressure,height and body quality testing,calculating body mass index(BMI),electro-cardiogram(ECG),echocardiography examination,blood routine,routine urine and biochemical examination).The CYP11B2 gene polymorphism used multiple stepwise regression analyses with correlation between gene and left ventricular hypertrophy.SPSS 22.0 statistical software was used for data analysis.Results:1.General clinical data of the subjects:In this study,434 subjects were included as follows:171 males and 263 females,with an average age of65.32±4.32 years.2.Genotyping results of CYP11B2:After genotyping,149 cases(34.3%)of TT,232 cases(53.5%)of CT and 53 cases(12.2%)of CC genotypes were distributed in the three genotypes.T allele 60.9%,C allele 39.1%.There was no statistical significance in the comparison of general information of patients with 3 genotypes(P>0.05).3.Multiple stepwise regression analysis:The left ventricular posterior wall thickness,left ventricular mass index(LVMI)and left ventricular mass in CC genotypes with-344C/T locus were significantly higher than those in CT and TT genotypes[(11.46±0.97)mm vs.(10.01±0.95)mm,(10.18±0.89)mm,P=0.000,(95.39±20.76)g/m~2vs.(84.73±12.68)g/m~2,(79.81±14.53)g/m~2,P=0.000,(174.69±31.27)g vs.(151.85±16.24)g,(146.08±19.08)g,P=0.007).Multiple stepwise regression analysis showed that the C-344T genotype was strongly associated with LVMI after adjustment for age,sex,type of antihypertensive drugs taken,BMI,smoking history,alcohol consumption history,TG,TC,LDL-C,HDL-C,heart rate,blood pressure,and fasting blood glucose(P<0.001).4.Comparison of the occurrence of cardiovascular events and the follow-up of death:After a mean follow-up period of 3.60±1.12 years,the incidence of MACEs was significantly higher in CYP11B2 CC genotype than in CT and TT genotype patients.Summary:CYP11B2-344C/T had gene polymorphism,and the C allele may have been an independent risk factor for left ventricular hypertrophy in patients with hypertension.Chinese elderly patients with essential hypertension CC genotype had a higher risk of cardiovascular events and death,which may have been associated with LVH in patients with essential hypertension CC genotype.Part Three Relationship between-344C/T polymorphism of CYP11B2gene and atrial fibrillation in Chinese patients with hyper-tensionObjective:CYP11B2 gene-344C/T polymorphism and the correlation of atrial fibrillation:The correlation studies of patients with essential hyperte-nsion(EH)reported less atrial fibrillation,but the results were inconsistent.The genotype frequency was obviously affected by outside factors such as race,gender,environment influence and could lead to differences.In the study of this section,the assessment of China's population center room fibrillation patients with the correlation of essential hypertension and CYP11B2 gene-344C/T polymorphism was explored.The results provided a molecular genetic basis for the differences in genetic susceptibility and drug responsiveness of patients with atrial fibrillation and hypertension.Methods:Hebei Province People's Hospital and Beijing Xuanwu Hospital continuously recruited patients from May,2017 to November,2020cardiology outpatient and Cardiology outpatient and wards were provided records of 310 cases with atrial fibrillation patients with essential hypertension.Those records were matched with the records of 310 cases of hypertension patients without AF.(For each case,a match in the same period not in EH patients with atrial fibrillation was chosen as a control).Patients in the two groups were independent and matched for sex and age,with age differences of no more than 5 years.In this study,all subjects were included in a detailed medical history,physical examination,and completion of relevant tests:blood pressure,height and body mass test,calculation of body mass index(BMI).The left atrium and left ventricle dimensions were measured by M-mode echocardiography and two-dimensional transthoracic echocardiography.The left ventricular ejection fraction(LVEF)was assessed by Simpson method,and the left ventricular mass was calculated according to the parameters of echocardiography and Devereux formula.CYP11B2 gene polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)assay to determine genotyping,and the correlation between genes and left ventricular hypertrophy was analyzed by multiple stepwise regression.Risk factors of atrial fibrillation were analyzed by Logistic regression.SPSS 22.0 statistical software was used for data analysis.Results:1.General clinical data of the subjects:In this study,there were 310patients in the experimental group(hypertensive atrial fibrillation),including158 males and 152 females,with an average age of 61.9±9.8 years;There were 310 patients in the control group(hypertension without atrial fibrillation),including 158 males and 152 females,with a mean age of 61.5±9.6years.There was no statistical significance in age,blood pressure,gender distribution,frequency of diabetes,smoking and drinking habits between the 2groups(P<0.05).The left atrial diameter(LAD)of patients with atrial fibrillation was significantly greater than that of controls(P<0.001).Similarly,ventricular septal(IVS)thickness,left ventricular end-diastolic size(LVEDD),and left ventricular mass were significantly higher in patients with atrial fibrillation than in controls(P<0.001).There was no significant difference in left ventricular posterior wall(LVPW)thickness and LVEF between the two groups(P>0.05).2.Genotyping results of CYP11B2:After genotyping,the percentages of the three genotypes(TT,TC and CC)in the experimental group were 41.9%,50.6%and 7.4%,respectively.The distribution in the control group was 48.4%,44.5%and 7.1%,respectively(?~2=2.675,P=0.263).The C allele frequency of CYP11B2 gene showed no significant difference between the experimental group(32.3%)and the control group(29.4%)(?~2=1.661,P=0.197).3.Multiple stepwise regression analysis:Logistic regression analysis showed that LAD and LVEDD were independent predictors of atrial fibrillation in Chinese patients with hypertension(P<0.001).The atrial fibrillation in C allele carriers was RR=1.30,95%CI:0.95-1.78,P=0.107;After adjustment for LAD and LVEDD,RR=1.13,95%CI:0.72-1.78,P=0.601).These results indicated that no association was found between-344C/T polymorphisms of AF and CYP11B2 in this population.4.Echocardiographic parameters of different genotypes:For a few CC genotypes,TC and CC genotypes as a group of C allele carriers were identified.LAD of C allele carriers was significantly higher than that of non-C allele carriers(P=0.009),but there were no significant differences in LVPW,IVS,LVEDD and LV quality between the two groups(P>0.05).Summary:The-344C/T polymorphism of CYP11B2 gene was not associated with non-familial atrial fibrillation in Chinese hypertensive population,but this polymorphism may be associated with atrial remodeling in Chinese hypertensive population.Larger clinical or experimental studies may be needed to confirm the role of aldosterone synthase in nonfamilial atrial fibrillation,as well as the role of genetic variations in aldosterone synthase genes in atrial fibrillation.Part Four Effect of-344C/T polymorphism of CYP11B2 gene and angio-tensin receptor antagonist on the treatment of hypertension in Chinese patientsObjective:Study of Chinese patients with high blood pressure CYP11B2gene-344C/T polymorphism of angiotensin II receptor:The antagonist telmisartan evaluation of the effects of the curative effect of treatment in patients with hypertension,was implemented.High blood pressure patients were to get China crowd CYP11B2 gene-344C/T polymorphism to combat the effects of high blood pressure medication.The guidance of genes for clinical evaluation provided the basis for individualized treatment.Methods:A total of 164 patients diagnosed with essential hypertension were enrolled in the outpatient department and ward of Hebei Provincial People's Hospital and Beijing Xuanwu Hospital from June,2016 to May,2019to conduct a clinical investigation,genotyping,and evaluation of the clinical efficacy of telmisartan in the treatment of hypertension.The subjects'general clinical data were collected,including age,sex,weight,height,blood pressure,heart rate(HR),and baseline data of the study variables.The study variables included serum ALT,creatinine,glucose,uric acid,total cholesterol,glyceride,HDL and LDL,sodium,potassium,and angiotensin II.All patients were given placebo after discontinuation of all was administered orally once daily at80mg/dose for 8 weeks.In the clinical trial,blood was drawn and blood pressure measured twice before and after telmisartan treatment.CYP11B2gene polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)to determine genotyping.Linear regression model was used to determine the correlation between BP response and genotype normalized with pretreatment BP,age,sex,BMI,blood glucose,TC,TG,HDL and LDL.SPSS 22.0 software was used for data statistical analysis.Results:1.General clinical data of the subjects:Data of 148 patients were included in this study.All patients were diagnosed with mild to moderate hypertension.After 8 weeks of telmisartan treatment,SBP and DBP were significantly reduced(P<0.001).Serum angiotensin II levels were significantly higher at the end of 8 weeks of treatment(P<0.001).There was no significant difference in other parameters.2.The antihypertensive response of C YP11B2-344C/T polymorphism to temisartan:The genotype and allele frequencies of each polymorphism in this study population were in Hardy-Weinberg equilibrium(P>0.05).3.CYP11B2-344C/T gene polymorphism and efficacy of antihyper-tensive therapy:In subjects with homozygous CYP11B2-344C alleles,linear regression analysis showed that CYP11B2-344C/T polymorphism was associated with DBP response to telmisaran,after adjustment for covariates including pre-treated DBP,age,sex,BMI,blood glucose,TC,TG,HDL and LDL(P=0.005).CYP11B2 gene-344C/T polymorphism accounted for 18.1%of the interindividual variation in the DBP response to telmisartan.Patients with the CYP11B2-344C allele(CC+CT)showed a greater decrease in DBP than those with the TT genotype.Summary:CYP11B2 gene-344C/T polymorphism may be effective treatment in China against hypertension and provide important clinical significance.Patient's blood pressure drug telmisartan may have a curative effect with certain genetic factors.Detection of specific genotypes could predict efficacy of certain antihypertensive drug treatment for clinical medicine programs,improve curative effect,and reduce the occurrence of cardiovascular events. |
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