Role of tagged SNPs of the AGT gene in causing susceptibility to essential hypertension

Aim: Angiotensinogen (AGT) is one of the candidate genes that has been extensively investigated for association of its variants with essential hypertension. Studies focusing on the contribution of tagged single nucleotide polymorphisms (SNPs) in the AGT gene are limited and lacking from Indian population. Hence, the present study was carried out to examine the role of five tagged SNPs viz., g.6147G>A (rs7539020), g.5978A>G (rs2493134); g.6241T>C (rs1078499), g.7781G>T (rs11122577), and g.5855G>A (rs3789678) in the development of hypertension. Materials and Methods: 202 hypertensives and 222 normotensives were screened for five tagged SNPs using the method of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results: The present study revealed significant association of g.5855G>A polymorphism with essential hypertension in different logistic regression models wherein protection was conferred by g.5855G>A against developing the condition. The polymorphism led to the creation of new exonic splicing enhancer and destruction of exonic splicing silencer site thereby enhancing the process of mRNA splicing. The haplotypes AGTG and GACG were found to have a significant protective effect. Other polymorphisms did not show any significant association with hypertension. Conclusion: The present study is the first one to report the protective role of g.5855G>A polymorphism in the development of essential hypertension. The results reflect possibility of ethnic variation in the contribution of g.5855G>A polymorphism of the AGT gene to essential hypertension.     

Haplotype association and synergistic effect of human aldosterone synthase (CYP11B2) gene polymorphisms causing susceptibility to essential hypertension in Indian patients

Background: Aldosterone synthase (CYP11B2) is a key enzyme involved in the terminal steps of aldosterone biosynthesis. Genetic variability in CYP11B2 gene has been associated with heterogeneous aldosterone production, which can affect sodium homeostasis and thereby regulation of blood pressure. Hence, the present study was aimed to explore the single-locus variations, haplotype and epistasis patterns of CYP11B2 (C-344T, intron-2 gene conversion and Lys173Arg) gene polymorphisms, and the risk contributed by them to the development of essential hypertension (EHT). Methods: A total of 279 hypertensive patients and 200 normotensive controls were enrolled in this study. C-344T and Lys173Arg polymorphisms of CYP11B2 gene were genotyped by PCR-RFLP method and intron-2 gene conversion (IC) polymorphism by allele-specific PCR analysis. Results: Single-locus analysis revealed significant association of CYP11B2 C-344T and Lys173Arg polymorphisms with EHT (p < 0.05). Considering the sexes, Lys173 allele was found to be at risk for hypertension in males (OR 1.40; 95% CI = 1.01–1.96). Unphased haplotype analysis revealed H1 (T-Conv-Lys; p = 0.0017) to have significant risk for EHT, while haplotype H4 (T-Wt-Arg) had a significant protective effect. Multifactor dimensionality reduction (MDR) interaction analysis found the overall best model with C-344T and IC polymorphisms exhibiting strong synergistic effect. Conclusion: The present study revealed a strong synergistic effect of CYP11B2 C-344T and IC polymorphisms causing susceptibility to EHT and haplotype H1 (-344T-Conv-Lys173) as the risk-conferring factor for hypertension predisposition.     

Genetic variations of beta 2-adrenergic receptor gene are associated with essential hypertension in Xinjiang Kazakans

Objective The aims of the present study were to investigate the associations of 46 A〉G, 79 C〉G, 491 C〉T and 659 C〉G genetic variants of the human beta 2-adrenergic receptor （β2-AR）, ADRB2, gene with essential hypertension （EH） in Xinjiang Kazakans population.Methods A gender-matched case-control （271 hypertensive cases and 267 normotensive controls） study was used to investigate the associations of the four variations in the coding region of ADRB2 with EH. The genotypes of the variants were identified by the polymerase chain reaction and restriction fragment length polymorphism （PCR-RFLP） methods. Results 46 A〉G, 79 C〉G and 659 C〉G polymorphisms were common in the Kazakan population, but 491 C〉T was a mutation （frequency ofT allele was only 0.003） and only found in EH group. The fxequency distributions of genotypes and alleles for 659 C〉G between the EH and control groups was significantly different （P〈0.05）, while those for 46 A〉G and 79 C〉G polymorphisms were not statistically different. Logistic regression analysis suggested that the G allele of 659 C〉G polymorphism was a risk factor for hypertension （minor allele vs common homo; odds ratio, 13.240, 95% CI, 4.052-43.274; P〈0.05）. Covariance analysis showed that systolic and diastolic blood pressure levels in GG＋CG group of 659 C〉G were significantly higher than those in the CC group, but no significant difference of blood pressure were found between common homo and minor allele for 46 A〉G and 79C〉G polymorphisms. Haplotype analysis showed that two hyplotypes, HI： 46A-79C-491C-523C（48%）and H5：46A-79C-491C-659G, were associated with EH.Conelusion ADRB2 genetic variants may play independent roles in the molecular genetic mechanism of EH in Xinjiang Kazakans population （d Geriatr Cardio12010; 7：52-57）.     

Polymorphism of the DNA methyltransferase 1 gene is associated with the susceptibility to essential hypertension in male

Essential hypertension is a leading global public health issue, billions of people suffered from it every year. Recently, multiple evidence suggests that DNA methylation play an important role in regulating blood pressure. Here, we tested the risk for essential hypertension conferred by single nucleotide polymorphisms (SNPs) within DNA methyltransferase 1 (DNMT1). Three loci (rs2228611, rs2228612, and rs16999593) were selected to be analyzed in 3410 cases and 1307 normal controls in southern Chinese aged 60 or above. No significant association with essential hypertension was observed for rs2228612 and rs16999593. A higher risk of essential hypertension was found in the minor A allele of rs2228611 in the codominant and recessive model (P < 0.05). After stratified by sex, this association was found in male but not female. Furthermore, this difference was abolished after BMI adjustment in the whole population and reduced in male. In addition, the mutation rate of rs2228611 was higher in the obesity group compared with the normal weight group of male. Intriguingly, rs2228611 was also a risk factor of essential hypertension in normal weight male. These findings indicated that rs2228611 might contribute to male hypertension via BMI-dependent mechanisms in obesity male and BMI-independent mechanisms in normal weight male.     

Replication of a genome-wide association study on essential hypertension in Mongolians

Replication of genome-wide significant association SNPs in independent populations is an essential approach for identifying gene–disease relationships. Therefore, we sought to investigate the top 21 SNPs (rs10507454, rs11897156, rs11897991, rs12325203, rs12541835, rs13395322, rs1525035, rs16936892, rs17010027, rs17045859, rs17136827, rs1866525, rs2045590, rs4547758, rs4655688, rs7107438, rs761353, rs8127139, rs9312305, rs9407874 and rs9865108) from a genome-wide association study of essential hypertension in Mongolians. This was a community-based case-control study involving 428 hypertensives and 638 normotensives from Kerqinzuoyihou Banner,Tongliao, Inner Mongolian Autonomous Region, China. Genotyping was conducted with Sequenom MassArray (®) SNP detection technology. Overall, there were no significant differences in the genotype distributions and allele frequencies between the cases and controls. There was a significant difference between the allele frequencies at locus rs17010027 in cases (high systolic blood pressure) and controls in female (p = .036). There were significant differences in the distribution of genotypes and the allele frequencies at locus rs10507454 between cases (high diastolic blood pressure) and controls (p = .019 and p = .022, respectively) especially in male (p = .009 and p = .011, respectively). rs17010027 is associated with high systolic blood pressure in female, and rs10507454 is associated with high diastolic blood pressure especially in male of this Mongolian population.     

绝经后妇女MTHFR基因多态性位点联合作用与骨质疏松易感性的相关性分析

目的研究5,10亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)的2个多态性位点rs1801131 A1298C和rs1801133 C677T的联合作用与苏州地区绝经后妇女骨质疏松遗传易感性的相关性。方法对从苏州市城区随机抽取的261例45~70岁绝经后妇女进行流行病学调查、基础资料测量及桡骨远端骨密度测定,利用荧光定量PCR技术(TaqMan)进行基因分型。应用SAS 9.1.3统计软件进行统计分析,PHASE 2.0软件进行单倍型分析,应用广义多因子降维法(GMDR软件,version 0.7)检测位点-位点、位点-环境之间的联合作用。结果调整年龄、体质量指数(BMI)、腰臀比(WHR)及产次后,MTHFR基因rs1801133(C→T)的位点变异与骨质疏松的发生成正关联。与野生型rs1801133 CC基因型相比,突变纯合型rs1801133 TT及CT/TT型可以显著增加骨质疏松的发生风险[调整OR=2.63,2.37;95%CI=(1.20~5.77),(1.16~4.87)]。经1000次置换检验(Permutation test)方法校正后,该位点的基因型频率分布在病例组与对照组间仍存在统计学差异。单倍型分析结果显示,与最常见的单倍型CC相比,含突变等位基因rs1801131 A的单倍型AC可以显著降低绝经后妇女骨质疏松的患病风险[调整OR=0.60;95%CI=(0.39~0.90)]。广义多因子降维法结果显示,模型A1 A2(rs1801131,rs1801133)为最佳模型(交叉验证一致性10/10,P=0.0107)。结论 MTHFR基因rs1801133位点多态性与苏州地区绝经后妇女骨质疏松的发病风险存在明显关联;rs1801131位点可能与rs1801133位点产生联合作用,共同影响绝经后妇女骨质疏松的发生风险。     

Effective blood pressure treatment improves LDL-cholesterol susceptibility to oxidation in patients with essential hypertension

OBJECTIVES: LDL-cholesterol particles from hypertensive patients exhibit enhanced susceptibility to in vitro oxidation, an abnormality thought to increase cardiovascular risk. We tested whether blood pressure (BP) normalization can reverse this abnormality. DESIGN: Double-blind, randomized pharmacological intervention trial. SETTING: Clinical research centre. Subjects. A total of 29 nondiabetic, normolipidaemic patients with essential hypertension (BP= 151 +/- 3/99 +/- 1 mmHg) and 11 normotensive controls (BP=125 +/- 3/85 +/- 1 mmHg) matched for gender, age, obesity, glucose tolerance and lipid profile. Intervention. Anti-hypertensive treatment for 3 months with a calcium-antagonist in randomized combination with either an ACE inhibitor or a beta-blocker. MAIN OUTCOME MEASURES: Lag phase of copper-induced LDL oxidation, cell-mediated (human umbilical vein endothelium) generation of malondialdehyde (MDA) by LDL and vitamin E content in LDL. RESULTS: At baseline in hypertensives versus controls, lag phase was shorter (89 +/- 3 vs. 107 +/- 6 min, P < 0.04), MDA generation was higher (5.8 +/- 0.1 vs. 5.1 +/- 0.2 nmol L(-1), P=0.002), and vitamin E was reduced (6.40 +/- 0.05 vs. 6.67 +/- 0.11 microg mg(-1), P=0.03). At 3 months, BP was normalized (124 +/- 3/81 +/- 1, P < 0.0001 vs. baseline, P=ns versus controls), lag phase was prolonged (to 98 +/- 3 min, P=0.0005), MDA generation was reduced (5.6 +/- 0.1 nmol L-1, P = 0.001), and vitamin E was increased (6.53 +/- 0.05 microg mg(-1), P=0.003), with no significant differences between the randomized groups. CONCLUSIONS: In nondiabetic, nonobese, normolipidaemic patients with essential hypertension, LDL susceptibility to copper- and cell-mediated oxidation is increased. BP normalization is associated with a significant improvement, but not a full reversal, of this abnormality.     

Genetic variants of the class A scavenger receptor gene are associated with essential hypertension in Chinese

Background

The class A scavenger receptor, which is encoded by the macrophage scavenger receptor 1 (MSR1) gene, is a pattern recognition receptor (PPR) primarily expressed in macrophages. It has been reported that genetic polymorphisms of MSR1 are significantly associated with many cardiovascular events. However, whether it links genetically to essential hypertension (EH) in Chinese is not defined.

Methods

We performed an independent case-control study in a Chinese population consisting of 617 EH cases and 620 controls by genotyping three single nucleotide polymorphisms (SNPs) of MSR1.

Results

We found that rs13306541 and rs3747531 were significantly associated with an increased risk of EH with per allele odds ratio (OR) of 1.63 [95% confidence interval (CI): 1.27-2.09; P<0.001] and 1.29 (95% CI: 1.09-1.52; P=0.003), respectively. Individuals with 2-4 risk alleles had a 2.03-fold (95% CI: 1.48-2.78) increased risk of EH compared with those having none of the risk alleles (P for trend <0.001).

Conclusions

Our results indicate that genetic variants of MSR1 may serve as predictive markers for the risk of EH in combination with traditional risk factors of EH in Chinese population.     

国产尼索地平片治疗原发性高血压的疗效观察

本研究采用自身对照开放试验方法,观察国产尼索地平片对轻、中度原发性高血压患者的疗效和耐受性.共有268例患者进入研究,其舒张压在95-114mmHg之间.经过7—10天的观察期,给予国产尼索地平片10mg-20mg,每日2次.治疗6周后病人收缩压和舒张压分别从162.26±16.92mmHg和103.63±7.15mmHg降至139.90±12.65mmHg和88.36±9.10mmHg(P<0.005),降压显效率达75.37%(202/268),有效率达21.27%(57/268).总有效率达96.63%.不良反应多为轻中度头痛、面红、踝部浮肿等.其中60例患者接受了单用尼索地平片6个月的长期治疗,结果显示血压得到稳定的控制,平均收缩压和舒张压分别波动在136.3—141.2 mmHg和86.3—88.0mmHg.16例病人进行了24h动态血压监测,结果显示24h平均收缩压和平均舒张压分别从143.20±20.68mmHg和88.87±10.20mmHg降至136.87±13.58mmHg和84.93±9.66mmHg(p<0.05).由此可见,国产尼索地平片是一种有效且易于耐受的抗高血压药物.     

卡维地洛治疗老年轻中度原发性高血压疗效观察

目的本研究以高选择性β受体阻滞剂比索洛尔为对照药，研究了卡维地洛治疗轻中度原发性高血压的临床疗效及安全性。方法选择轻中度原发性高血压患者60例，分别随机给予卡维地洛和比索洛尔口服治疗。结果2组在治疗2周时诊室血压均有所下降，在治疗6～8周末下降最明显，并维持至24周。卡维地洛组和比索洛尔组降压总有效率分别为93．3％和90％，总显效率分别为70％和56．7％。卡维地洛主要的不良反应有头晕（13％）、乏力（2％）、嗜睡（2％）。在服药过程中逐渐减轻，无因药物不良反应而终止者。结论本研究中的原发性高血压患者每日口服1次卡维地洛12．5～50mg，降压疗效明显，耐受性及安全性好。     

Dose titration study of isradipine in Chinese patients with mild to moderate essential hypertension

Summary In order to assess the effective dose, tolerability, and safety of isradipine as a monotherapeutic antihypertensive agent for Chinese patients in Taiwan, an open trial was carried out. This study consisted of a 2-week, placebo, run-in period and an 8-week active treatment period, starting with isradipine 1.25 mg twice daily (bid) for the first 4 weeks, followed by 2.5 mg bid if the blood pressure was not normalized (diastole <90 mmHg). One hundred and one patients (M/F=48:53) were valid for efficacy analysis. Their age ranged from 30 to 64 years (mean±SD, 52±8). The blood pressure before active treatment was 160±2/104±1 mmHg. At the end of treatment period I (week 4), 12–14 hours after the last dose, 38 (37.6%) patients were normalized and 47 (46.5%) subjects responded (diastolic blood pressure reduction 10 mmHg). At week 8, 68 (67.3%) patients were normalized and 79 (78.2%) subjects responded. Isradipine reduced both systolic and diastolic blood pressures within 2 weeks of treatment. There were no significant differences in blood pressure reduction between both genders and among age groups. Safety analysis showed two subjects with severe flushing, dizziness, and palpitation who used the dose of 1.25 mg bid. They withdrew from the study. The adverse reactions of other patients were transient, mild, and tolerable. Most of the side effects were related to vasodilatation, but edema was not found. There was no change in body weight or heart rate, nor any atrioventricular conduction disturbances. In conclusion, isradipine in a dose of 1.25 or 2.5 mg bid proved to be an effective and well-tolerated antihypertensive agent for Chinese subjects in Taiwan with mild to moderate essential hypertension. This finding is similar to those reported in Caucasian patients.     

原发性高血压患者发生尿微量白蛋白列线图的构建和评价

目的:研究未治疗的原发性高血压患者发生尿微量白蛋白的危险因素,构建列线图预测模型并验证其有效性.方法:本研究连续纳入2018年1月—2019年12月在我院门诊和病房未治疗的原发性高血压共456例患者.随机分为建模组(318例)与验证组(138例).以上述指标构建列线图模型,在建模组中,应用LASSO回归和非条件二分类L...     

坎地沙坦和苯那普利治疗高血压病的对照研究

目的评价坎地沙坦同苯那普利治疗高血压病的疗效及其对血脂、肾功能的影响及副作用。方法坎地沙坦组59例给予坎地沙坦剂量816 mg/d,苯那普利组56例服用苯那普利,剂量1020 mg/d,均治疗6周。治疗前后所有参与者测血压和测定胆固醇、三酰甘油、肾功能。结果监测血压显示坎地沙坦组降压与苯那普利组无差异,对胆固醇、三酰甘油没有影响,有降低尿酸的作用,与苯那普利组相比,咳嗽发生率低,并能改善肾功能及保护内皮细胞功能。结论坎地沙坦同苯那普利治疗轻、中度高血压病安全、有效,对血脂、肾功能无影响。坎地沙坦有降低尿酸的作用,咳嗽发生率低。     

Association between the calcitonin-related peptide alpha (CALCA) gene and essential hypertension in Japanese subjects

BACKGROUND: Calcitonin-related peptide alpha (CALCA) is a neuropeptide that is a very potent vasodilator. It has been reported that CALCA knockout mice have a significantly elevated systolic blood pressure (BP). The aims of this study were to discover novel polymorphisms or mutations in the 5' flanking region of the human CALCA gene in Japanese subjects and to assess the association between this gene and essential hypertension (EH). METHODS: Japanese patients with EH (50.1 +/- 6.6 years old, n = 274) and age-matched Japanese subjects without EH (51.1 +/- 6.6 years old, n = 225) were recruited. The 5' flanking region of the human CALCA gene was searched to identify novel polymorphisms in the 20 EH patients using polymerase chain reaction (PCR) and a direct sequencing method. These novel polymorphisms, as well as the known single nucleotide polymorphisms (SNPs), were used for genotyping. RESULTS: We discovered a novel 2-bp microdeletion polymorphism in intron 1. The only three participants with 2-bp microdeletion polymorphism were found in the EH group. None of the subjects without EH had a 2-bp microdeletion polymorphism. The genotype and allele distribution of the 4 SNPs were not significantly different between the groups. All five polymorphisms were located in one haplotype block. The haplotype was constructed using, in order, rs1553005, 2-bp microdeletion polymorphism, and rs5241. There was a significant association between EH and the C-AGins-A haplotype (P = .00031). CONCLUSIONS: A novel 2-bp microdeletion polymorphism was discovered in the CALCA gene. Based on the results of the haplotype-based case control study, the CALCA gene could be the susceptibility gene for EH.     

肥胖原发性高血压伴高胰岛素血症患者血管紧张素原基因rs7079变异与福辛普利降压疗效的关系

目的 分析血管紧张素原（AGT）基因rs7079（C／A）与福辛普利在伴高胰岛素血症的肥胖原发性高血压（EH）患者中降压疗效的相关性。方法以福辛普利（10mg,1次／d）治疗70例伴高胰岛素血症的肥胖EH患者,疗程4周。检测AGT基因rs7079（C／A）的基因型,分析其与降压效果及IS相关指标的关系。结果AGT基因rs7079（C／A）位点C、A等位基因频率分别为77．14％、22．86％,其中,CC基因型患者43例,AC＋AA基因型患者27例。与治疗前相比,两组基因型患者治疗4周后SBP、DBP均下降（P〈0．05）,CC基因型患者SBP低于AC＋AA基因型患者[（126．16±1．93）vs（133．00±2．40）mmHg,P〈0．053。未发现AGT基因rs7079（C／A）基因型与IS有相关性。结论肥胖EH伴高胰岛素血症患者AGT基因rs7079（c／A）与福辛普利降压疗效相关,其中,cc基因型患者降SBP效果更好。     

髓过氧化物酶基因多态性与原发性高血压遗传易感性的研究

目的:研究髓过氧化物酶(MPO)基因多态性与原发性高血压(EH)之间的遗传易感性.方法:采用分子流行病学方法,应用聚和酶链反应检测法107例EH和97例健康对照MPO基因型,比较不同基因型之间的分布频率及95%可信区间(CI),分析MPO基因多态性与EH易感性的关系.结果:正常人群GG、GA、AA基因型频率分别为56 7%、40 2%和3 1%,EH组分别为70 1%、29 0%和0 9%.携带GG者患EH的风险是基因型为至少一个等位基因A者的1 79倍 (95%CI 1 005~3 186).结论:本研究人群MPO基因多态与EH遗传易感性相关,等位基因A对EH易感性有保护作用.     

间隙性连接蛋白37基因1019C/T多态性与原发性高血压的关系

目的 研究无锡地区人群中间隙性连接蛋白37 （connexin 37,CX 37）基因1019C/T多态性与原发性高血压的相关性.方法 入选在无锡市人民医院初次诊断为原发性高血压的患者1 126例,874名健康体检者作为正常对照组,均采用基因测序技术对CX37基因1019多态性位点基因型进行检测,比较两组人群中基因型及等位基因分布差异.结果 （1）两组人群中均存在CX 37基因1019C/T多态性,基因型分布均符合Hardy-Weinberg遗传平衡定律.（2）原发性高血压组与正常对照组相比,C等位基因分布频率升高（57.37％vs.42.05％,P＜0.01）.C等位基因携带者（CC＋TC）在原发性高血压组高于对照组,差异有统计学意义（80.46％ vs.66.70％,P＜0.01）.与Tr纯合子相比,（CC＋TC）基因型原发性高血压患病风险增加（OR=2.06,95％ CI：1.68～2.52）.对性别进行亚组分析显示：无论男性还是女性人群中原发性高血压组C等位基因携带者频率均显著高于正常对照组（男性：79.19％vs.69.05％,P＜0.01;女性：81.75％ vs.64.40％,P＜0.01）,C等位基因携带者原发性高血压患病风险明显高于TT型（男性：OR=1.71,95％CI：1.28～2.27;女性：OR=2.48,95％ CI：1.85～3.31）.结论 CX37 C等位基因可能与老年原发性高血压相关.     

原发性高血压患者主动脉夹层钙化特点分析

目的分析原发性高血压患者主动脉夹层(AD)的血管钙化(VC)特点。方法选择2010年1月至2015年12月于中山大学孙逸仙纪念医院住院的原发性高血压并经过主动脉计算机断层扫描血管造影(CTA)确诊为AD的30例患者为AD组,原发性高血压且主动脉CTA提示无主动脉病变者30例为对照组。通过CTA和Agatston评分系统分析2组人群以及不同Stanford类型AD患者之主动脉钙化特点。结果与对照组比较,AD组降主动脉VC发生率升高(P0.05),主动脉弓VC发生率下降(P0.05)。2组Agatston评分及不同程度VC发生率的差异无统计学意义(均P0.05)。AD组患者分为Stanford A型及Stanford B型2个亚组。2个亚组的临床资料、主动脉及不同部位VC发生率差异无统计学意义(均P0.05)。多因素Logistic回归分析显示,与AD病变相关的因素有:低密度脂蛋白胆固醇(OR=3.397,95%CI 1.234～9.354,P=0.018)、不规律服用降压药(OR=20.417,95%CI2.326～179.233,P=0.006)、主动脉弓VC发生率(OR=0.027,95%CI 0.002～0.357,P=0.006)及降主动脉VC发生率(OR=35.606,95%CI 2.475～512.27,P=0.009)。结论原发性高血压患者主动脉不同部位钙化特点不同可能是高血压促进AD病变的重要环节。