内皮型一氧化氮合成酶基因多态性与原发性高血压的相关性

高血压是最常见的慢性病,也是心脑血管病最主要的危险因素,目前其发病率呈上升趋势[1,2].原发性高血压（essential hypertension,EH）是受遗传因素与环境因素共同影响的慢性疾病.近年来研究表明,遗传因素在原发性高血压的发生、发展中起着更重要的作用.内皮型一氧化氮合酶（endothelium nitrogen monoxide synthase,eNOS）是高血压的易感因素,它的基因编码所产生的一氧化氮（nitrc oxide,NO）具有调节血管张力、血管重塑、维持血管内皮的完整性等作用.随着血管生物学与临床医学领域联合研究的不断深入,在心血管疾病中研究调查调控高血压基因已成为热点.国内外研究表明,eNOS基因在原发性高血压中发挥重要作用.本文对eNOS基因G894T、T786C和27bpVNTR的多态性影响EH的机制及与EH相关性最新研究进展作一综述.     

Association of essential hypertension with a microsatellite marker on chromosome 17

Hypertension is related to sodium intake, and many patients with essential hypertension are overweight and have the metabolic syndrome. We therefore studied microsatellite markers close to the thiazide-sensitive Na-Cl cotransporter on chromosome 16 and a quantitative trait locus for abdominal obesity-metabolic syndrome (AOMS2) on chromosome 17, which have been found to be linked to hypertension in a previous genome scan in Chinese. There were 84 hypertensive subjects (44 men, 40 women, age 53+/-13 years) and 88 normotensive controls (40 men, 48 women, age 54+/-13 years) recruited. Specific oligonucleotide primers were used to amplify genomic DNA spanning the microsatellite markers D16S3396 and D17S1303 that consist of ATA and GATA repeats, respectively. We did not find any association between D16S3396 and blood pressure. In contrast, the distribution of D17S1303 genotypes differed between hypertensive subjects and normal controls (P = 0.014). The number of GATA repeats correlated inversely with diastolic blood pressure (r = -0.18, P = 0.02) and body mass index (r = -0.12, P = 0.01). Nine GATA repeats in D17S1303 were associated with hypertension (OR 2.19, 95% CI 1.08-4.44, P = 0.027), while 14 GATA repeats were associated with normotension (OR 0.26, 95% CI 0.10-0.66, P = 0.002). The diastolic blood pressure in those with or without the (GATA)9 allele was 85.9+/-13.6 and 79.2+/-13.6 mmHg respectively (P = 0.01), and in those with or without the (GATA)14 allele it was 73.8+/-11.0 and 81.8+/-14.0 mmHg respectively (P = 0.003). Our results provide further evidence that a gene predisposing to hypertension in Chinese is in the vicinity of the microsatellite D17S1303.     

Association of TNFRSF4 gene polymorphisms with essential hypertension

BACKGROUND: Essential hypertension is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. The TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) gene was one of the genes that showed altered renal expression in long-term salt loading in mice. Moreover, association of the TNFRSF4 and TNFSF4 (tumor necrosis factor (ligand) superfamily, member 4) genes with myocardial infarction was recently reported. Since essential hypertension is a well-known risk factor for myocardial infarction, we hypothesized that TNFRSF4 could be a susceptibility gene for essential hypertension. METHODS: We performed a case-control study of TNFRSF4 in two independent population. RESULTS: Extensive investigation of single nucleotide polymorphisms of the entire gene suggested that it resided in one linkage disequilibrium block, and four single nucleotide polymorphisms in the 5' flanking region sufficiently represented major haplotypes. In the combined population, the frequency of the most frequent haplotype, C-C-A-A, was significantly lower (P = 8.07 x 10(-5)) and that of the second most frequent haplotype, C-T-G-A, was significantly higher (P = 6.07 x 10(-4)) in hypertensive subjects than in control subjects. This difference was observed only in female patients. The C-T-G-A haplotype showed a lower promoter activity than other haplotypes, suggesting a relationship with disease susceptibility. CONCLUSION: Our results suggest that TNFRSF4 is a female-specific susceptible gene for essential hypertension.     

ACE2基因多态性与原发性高血压的关系

目的 研究血管紧张素转化酶2（angiotensin converting enzyme 2,ACE2）基因多态性与广东地区原发性高血压的相关性.方法 高血压组选择门诊与住院的汉族无血缘关系的原发性高血压369例,男194例,女175例;对照组为同期体检的广东地区健康汉族居民199例,男101例,女98例.排除冠心病、高血压、糖尿病、脑血管病及肝功能不良、肾功能不良.按照性别分为两组,采用病例对照的原则,应用聚合酶链反应和限制性内切酶片段长度多态性（polymerase chain reaction and restriction fragment length polymorphism,PCR-RFLP）的方法检测ACE2基因G9570A多态性,并随机抽取20份标本进行基因测序以核实基因分型.在分析各亚组的年龄、体重指数、血压及生化指标的基础上综合分析ACE2基因多态性与原发性高血压的关系.结果 高血压组G等位基因频率：男75.3%,对照组男60.4%,差异有统计学意义（χ2=7.0086,P=0.0081）,高血压组,女57.4%,对照组45.4%,差异有统计学意义（χ2=6.9443,P=0.0084）;女高血压组GG基因型的频率明显高于对照组（χ2=12.9499,P=0.0015）;G等位基因人群发生高血压的风险高于A等位基因人群,男OR：1.9945,95% CI：1.1916～3.3385,P=0.0082;女OR：1.603,95% CI：1.1274～2.2792,P=0.0085.结论 ACE2-G9570A多态性与原发性高血压相关;携带G等位基因的男性和仅仅携带G基因的女性人群发生高血压的危险性相对较大,提示ACE2基因可作为原发性高血压的候选易感基因.     

原发性高血压患者子代人群载脂蛋白E基因多态性与高血压的关系

目的 探讨原发性高血压患者子代人群载脂蛋白E(ApoE)基因多态性与高血压的关系.方法 应用聚合酶链反应—限制性片段长度多态性技术检测60例血压正常的原发性高血压患者子代(研究组)和60例正常对照者(对照组)的ApoE基因多态性,并分析其多态性与高血压的关系.结果 所有研究对象的PCR片段均得到满意扩增,共检测出6种基因型,经Hardy-Weinberg平衡检验均达到连锁平衡,具有群体代表性.两组均以ApoE3/3为优势基因型,但两组各基因型比较差异均无统计学意义(P均＞0.05).两组均以ε3等位基因频率最高,ε2等位基因最低;研究组ε4等位基因频率高于对照组(x2=12.42,P＜0.05).结论 原发性高血压患者子代人群高血压的易感基因为ApoEε4等位基因.     

内皮型一氧化氮合酶基因rs3918181位点多态性与原发性高血压的关系研究

目的 探讨天津市汉族人群内皮型一氧化氮合酶(eNOS)基因第14内含子rs3918181位点多态性与原发性高血压(EH)的关系.方法 采用聚合酶链反应-限制性内切酶片段长度多态分析法(PCR-RFLP)对290例EH患者和161名健康对照者的eNOS基因rs3918181位点进行基因多态性分型,同时检测所有研究对象的血脂等危险因素,分析不同基因型与EH发病的关系.结果 两组年龄、体质指数的差异有统计学意义(均为P＜0.05).EH组患者的AA、AG和GG基因型分布频率分别为0.293、0.393和0.314,对照组分别为0.180、0.472和0.348,两组相比差异有统计学意义(均为P ＜0.05);EH组A与G等位基因频率分别为0.490和0.510,对照组分别为0.416和0.584,两组相比差异有统计学意义(均为P ＜0.05).影响EH的危险因素有年龄、体质指数.结论 eNOS基因rs3918181位点多态性与EH相关.     

Association study of calcitonin-receptor-like receptor gene in essential hypertension

BACKGROUND: Plasma adrenomedullin (ADM) concentrations increase in patients with hypertension, renal failure, heart failure, essential pulmonary hypertension, myocardial infarction, endotoxin shock, and many other conditions. The ADM receptor is a complex molecule that consists of calcitonin-receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2). Because CRLR determines the binding specificity of ADM, the CRLR gene is thought to be a susceptibility gene of hypertension. However, studies have not yet defined the relationship between the CRLR gene and hypertension. The aim of the present study was to investigate relationships between single-nucleotide polymorphisms (SNP) in the human CRLR gene and essential hypertension (EH) in a Japanese population. METHODS: We selected four SNP in the human CRLR gene (rs3771073, rs696574, rs698590, and rs1528233), and we performed a genetic association study in 209 EH patients and 216 age-matched normotensive (NT) individuals. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNP between the EH and NT groups. However, among women, the T allele of the SNP rs696574 (C --> T, in intron 6) was significantly more frequent in EH subjects than in NT subjects (P = .032). CONCLUSION: Our findings suggest that rs696574 can be used as a genetic marker of EH in women.     

瘦素受体基因Gln223Arg多态性与原发性高血压相关性研究

目的:研究高血压候选基因瘦素受体基因(LEPR)在中国北方汉族人群的分布,探讨LEPR基因Gln223Arg多态性与原发性高血压(EH)的关系。方法:采集健康体检人群临床资料,分析体质量指数、血脂、血糖等临床指标,同时调查受检者吸烟和饮酒等生活习惯;Taq Man-MGB法分析LEPR基因Gln223Arg多态性在中国北方汉族人群(样本总数1 273例,其中原发性高血压病患者774例,血压正常的健康体检者499例)的分布及其与临床指标的相关性。结果:LEPR基因Gln223Arg基因型在两组总体的差异具有统计学意义(P=0.036)。按照血尿酸水平进行亚组分析,高尿酸亚组基因型(P=0.039)和等位基因频率(P=0.037)的差异具有统计学意义;调整相关因素的影响后,多因素Logistic回归模型分析显示:LEPR基因Gln223Arg多态性与EH相关[(GG+AG)vs.AA模型,OR=3.23,95%CI:1.01~10.34,P=0.008;GG vs.AA模型,OR=3.43,95%CI:1.35~8.75,P=0.010];高尿酸亚组也显示该多态性与EH发病密切相关[G vs.A模型,OR=1.89,95%CI:1.09~3.28,P=0.023;(GG+AG)vs.AA模型,OR=7.76,95%CI:1.18~49.80,P=0.033;GG vs.AA模型,OR=8.50,95%CI:1.29~56.12,P=0.026;GG vs.AG vs.AA模型,OR=1.94,95%CI:1.10~3.43,P=0.023]。结论:在中国北方汉族人群中,LEPR基因Gln223Arg多态性与原发性高血压相关。     

eNOS基因多态性与湖北汉族人群原发性高血压相关

采用聚合酶链反应结合聚丙烯酰胺凝胶电泳检测湖北汉族316例原发性高血压患者和338名正常人内皮型一氧化氮合酶(eNOS)基因第4内含子多态性,发现eNOS基因该位点多态性(ab+aa等位基因)与原发性高血压显著相关(P＜0.05),可能是湖北汉族人群原发性高血压的一个易感标记.     

ACE基因多态性与老年人原发性高血压的关系

目的 探讨血管紧张素Ⅰ转换酶（ACE）基因多态性与老年人原发性高血压（EH）的相关性。方法 采用一步PCR3条引物法,对287例老年EH（高血压组）和301例正常老年人（对照组）进行ACE基因I／D多态性分型,并进行基因型及等位基因频率计数,组间采用χ^2检验进行统计学分析。结果 高血压组DD型基因频率及D等位基因频率分别为10．4％和30．5％,对照组分别为9．3％和31．2％,经χ^2检验,2组间无显著差别（P＞0．05）。结论 ACE基因多态性与老年人原发性高血压（EH）无关。一步PCR3条引物法更准确可靠,可减少DD型错判率。     

血管紧张素转化酶1基因单倍型与原发性高血压

目的:研究中国人群中血管紧张素转化酶1(ACE1)基因多态性及单倍型与原发性高血压的关系。方法:在298例原发性高血压患者(病例组)与199例血压正常人(对照组)采用PCR后的限制性酶切片段长度多态性(PCR-RFLP)法或电泳直接检测ACE1基因8个位点多态性,同时用最大期望值(EM)计算法进行2位点连锁不平衡(LD)状态和单倍型类型的估计。结果:ACE1基因多态存在LD(均D'>0.5),8个多态存在于常见的9个单倍体中,其中2种最常见的单倍型为A(A-T-A-T-G-I-A-3)和B(C-C-T-C-A-D-G-2),A和B在每个位点都不相同。单个位点除A-240T外,其余各位点均未见与高血压有关联,单倍型D的频率在病例组中高于对照组。结论:该群体中ACE1基因存在LD,T-240位点可能为原发性高血压易感位点LD。     

Microalbuminuria, an integrated marker of cardiovascular risk in essential hypertension

This paper reviews the existing epidemiological and clinical evidence about the relationships of non-diabetic microalbuminuria with cardiovascular risk factors such as elevated blood pressure (BP), systolic particularly, cardiac hypertrophy, adverse metabolic status, smoking habits, elevated angiotensin II levels, endothelial dysfunction, acute and perhaps subclinical inflammation. Because of that unique property of reflecting the influence of so many clinically relevant parameters, microalbuminuria may legitimately be defined as an integrated marker of cardiovascular risk, an unique profile among the several prognostic predictors available to stratify risk in hypertensive patients. Recent cohort studies also showed associations with cardiovascular morbidity and mortality independently from conventional atherogenic factors. This behaviour, whose understanding still needs further elucidation, suggests to measure albuminuria and to screen patients at a higher absolute risk in whom preventive treatment is expected to be more beneficial than in those with a lower absolute risk.     

Association between hepatocyte growth factor gene polymorphism and essential hypertension.

Hepatocyte growth factor (HGF) is a growth factor which contributes to protection and/or repair of vascular endothelial cells. Serum HGF level is elevated in response to hypertensive organ damage, which suggests that blood pressure regulation may be affected by HGF gene polymorphisms via serum HGF. To examine the interaction between a HGF gene polymorphism and hypertension, we carried out a case-control study. The present study was conducted in outpatients of Osaka University Hospital. Subjects (n=654) who gave informed consent to the study protocol and genetic analysis were recruited. A C to A nucleotide substitution in intron 13 of the HGF gene was determined by the TaqMan polymerase chain reaction (PCR) method using an MGB (Minor Groove Binder) probe. The genotype distribution of the C/A polymorphism of the HGF gene in total subjects was as follows: CC, 83%; CA, 16%; and AA 1%. This distribution was not significantly different from the predicted by Hardy-Weinberg's equilibrium. The prevalence of hypertension was significantly higher in subjects with the CC genotype than in those with an A allele, and the positive association remained after adjustment for confounding factors, with the estimated odds ratio for hypertension (CC vs. CA+AA) being 1.71 (95% confidence interval: 1.02-2.93). A significant association with hypertension was observed in lean or female subjects but not in obese or male subjects. In conclusion, our data suggested that C/A polymorphism in intron 13 of the HGF gene is associated with susceptibility to essential hypertension in lean or female subjects.     

Association and linkage analyses of glucocorticoid receptor gene markers in essential hypertension

Suggestive evidence has been obtained in a "4-corners" study for involvement of the glucocorticoid receptor gene (GRL) in genetic variation in blood pressure. Therefore, we tested markers at the GRL locus for association and linkage with essential hypertension (HT). For the association study, we used a well-characterized group of 129 white Australians of Anglo-Celtic extraction who had HT, a strong family history of HT (2 parents with the disease), and early-onset moderate-to-severe disease. Controls were 195 normotensive white subjects whose parents were normotensive past the age of 50 years. For the linkage study, we used 175 sibling pairs of similar ancestry. The case-control groups were genotyped for an Asn363Ser variant in exon 2, a G/T variant in intron 4, and a microsatellite marker (D5S207) tightly linked (<200 kb) to GRL. For the groups as a whole, no association or linkage was observed after analysis of data by a variety of statistical tests. Analysis of sibling-pair data gave an exclusion score of -3.8 for the logarithm of the odds for linkage, indicating significant nonlinkage. However, in females, weak association of the intron 4 polymorphism with HT (P=0.03), as well as with systolic and diastolic blood pressure in all subjects (P=0. 04 and 0.03), was observed, and in the case of the D5S207 marker, association with HT was apparent in males (P=0.0001). Thus, although our results provide no overall support for GRL in HT etiology, apparent gender-specific associations could exist in this genomic region, possibly reflecting correlated occurrence with (an)other metabolic syndrome disorder(s).     

Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension

Endothelial nitric oxide synthase (eNOS), encoded by NOS3, is a potent regulator of vasomotor tone and peripheral resistance. Congenic experiments indicate that a chromosomal segment containing the rat eNOS gene contributes to rat spontaneous hypertension (HT). A role for NOS3 in onset of essential hypertension (HT) is, however, controversial. We therefore decided to test NOS3 polymorphisms in a set of patients who have an accentuated ability to show an existing genetic association. The 112 HT subjects had two HT parents and the normotensive (NT) subjects had two NT parents. All were Anglo-Celtic whites. The two most promising polymorphisms, viz, a biallelic variable number of tandem repeats (VNTR) in intron 4 and an exon 7 variant that leads to an amino acid change (Glu298Asp), were genotyped by PCR (and BanII digestion in the case of the latter). Frequency of the minor allele of the VNTR was 0.11 in the NT and 0.10 in the HT subjects (P = .9). For the exon 7 variant, Asp298 frequency was 0.30 and 0.32 in each respective group (P = .6). Tracking was seen for the Asp298 allele with elevation in body mass index (P = .034), and the minor allele of the VNTR with elevation in LDL (P = .007) and reduction in HDL (P = .048). In conclusion, we saw no association of NOS3 markers with HT in the population studied. However, possible genotypic effects on plasma lipids and body mass index might warrant further studies, especially in view of possible associations with heart disease.     

Association of paraoxonase 1 (PON1) gene polymorphisms and concentration with essential hypertension

Human serum paraoxonase 1 (PON1) is carried by high-density lipoprotein in blood circulation and is shown to be effective in preventing oxidized phospholipids carried by low-density lipoprotein particles, thus it acts as an antioxidant. Polymorphism in this gene has been investigated for many metabolic diseases, but it is not thought to be a genetic risk factor for essential hypertension. The aim of this study was to determine whether there was an association between PON1 gene polymorphisms and concentration with essential hypertension. The study population was comprised of 100 patients with essential hypertension and 100 healthy controls. One promoter region [C(-108)T] and two coding region (Q192R and L55M) polymorphisms in the PON1 gene were genotyped in individuals by using the TaqMan assay. Plasma PON1 concentration in all volunteers was also measured spectrophotometrically by the enzyme-linked immunosorbent assay method. The genotype and allele frequencies of the PON1 C(-108)T polymorphism showed significant differences between the essential hypertensive and control groups (CT vs. CC: p<0.001; T allele vs. C allele: p<0.001). There was no significant difference for the PON1 L55M polymorphism between the groups, while the heterozygote genotype of the PON1 Q192R polymorphism showed significant difference (p = 0.03). The PON1 concentration was also found to be significantly lower in hypertensive patients (p < 0.001). Decline in the level of PON1 gene may be one of the main factors in the development of essential hypertension, and the PON1 C(-108)T polymorphism may have a prognostic value in the patients with essential hypertension.     

Association of endothelial nitric oxide synthase gene G894T polymorphism with essential hypertension in an adult Pakistani Pathan population

This retrospective, case-control study was carried out to find putative correlations of eNOS G894T polymorphism with essential hypertension (EHT) amongst adult Pakistani Pathans. We investigated a sample population of 332 (154 men, 178 women) comprising groups of 146 hypertensives (HTs) and 186 normotensives (NTs) by assays based on polymerase chain reaction followed by restriction endonuclease analysis. The distribution of the genotypes or alleles was not statistically different in hypertensive and normotensive groups. In conclusion, the present study in a population of Pakistani adult Pathans does not support the association of the eNOS gene G894T polymorphism to essential hypertension.     

Lipid profile and apolipoprotein E polymorphism in essential hypertension

BACKGROUND: Studies in several populations have indicated that genetic variation at the apolipoprotein E structural locus influences atherosclerosis leading to cardiovascular diseases. The possible role of apolipoprotein E polymorphism in the development of essential hypertension has not been sufficiently investigated. In this case-control study, we aimed to determine the significance of association between essential hypertension and apolipoprotein E genotypes. In addition, apolipoprotein E genotypes were correlated with serum lipid levels in order to understand the possible interaction between the specific genotype and the lipid profiles that can contribute to hypertension. METHODS AND RESULTS: The apolipoprotein E genotypes were assayed in 185 patients and 200 controls by polymerase chain reaction followed by enzymatic digestion with Hha I. Using logistic regression analysis, the multivariate-adjusted odds of hypertension were calculated. The incidence of epsilon4 allele was found to be significantly higher in patients (12.16%) than in controls (5.75%, chi2=10.87; p<0.05) and also in patients with positive family history (16.7%) as compared to negative family history (8.87%, chi2 = 8.45; p<0.1). Further, it was observed that carriers of epsilon4 allele have twice as much risk (p<0.05) for developing hypertension as compared to carriers of other alleles. Patients with epsilon4 allele had significantly higher levels of total cholesterol and low-density lipoprotein- cholesterol as compared to epsilon4 allele non-carriers (p<0.05). The adjusted odds ratios for epsilon4 and epsilon2 alleles versus epsilon3 allele were 2.2 (95% confidence interval 1.2 to 3.8, p<0.05) and 1.2 (95% CI, 0.75 to 1.77, p<0.514), respectively. CONCLUSIONS: Our study revealed a strong association of apolipoprotein E locus with hypertension and lipid profile. However, large population-based studies are needed to understand the exact role played by the locus in causing the condition.