ET-1、eNOS基因多态性与江西汉族人群原发性高血压及硝苯地平降压疗效的相关性研究

发布时间：2018-05-06 18:32

本文选题：原发性高血压 + 内皮素-1　；参考：《南昌大学》2016年博士论文

【摘要】：目的：原发性高血压(essential hypertension, EH)是一种多基因遗传与环境因素相互作用的慢性疾患,且是冠心病、脑卒中等心脑血管疾病及终末期肾病的独立危险因素。许多研究证实,在人类的基因中存在着高血压病的易感基因。但目前为止,人们还没有发现某个人类基因的多态性与高血压的发生直接相关。既往的研究表明,内皮素-1(ET-1)表达增多能够增强动脉血管的阻力,高血压病患者血浆中ET-1水平明显高于血压正常者的人群,而且靶器官的损害更严重,提示ET-1可能会增加高血压病发生的风险；另外,人们还发现在高血压患者的动脉壁内有ET-1受体基因的过表达,这可能表明ET-1导致高血压发生的机制是通过影响内皮功的能障碍或促进血管平滑肌细胞增殖的方法来实现的;使用ET-1受体拮抗剂能够降低慢性高血压患者的血压,从而进一步证实ET-1与高血压存在明显的相关性。既往的研究也表明,一氧化氮(NO)在心血管疾病中发挥了重要作用,一氧化氮是在一氧化氮合酶(NOS)催化下生成的。三种不同的一氧化氮合酶在心血管疾病中的作用各不相同,通过对一氧化氮合酶的干预将成为心血管疾病治疗的新策略。鉴于上述的研究结果提示ET-1、eNOS与高血压的发生有关,因此,ET-1、eNOS基因已被认为是高血压病的高危候选基因。筛查原发性高血压相关基因的单核苷酸多态性,进行基因分型与疾病相关性研究及与降压疗效关系研究是对EH进行早期诊断、预防和治疗的基础。本论文分两章探讨：.初步探讨内皮素-1基因多态性与江西汉族人群原发性高血压及硝苯地平降压疗效的相关性。二.探讨内皮型一氧化氮合酶基因多态性与江西汉族人群原发性高血压及硝苯地平降压疗效的相关性方法：第一部分：对确诊为高血压病的423例患者和114例健康志愿者空腹静脉抽血分别用于血脂、血糖及ET-1浓度的检测及全基因组的提取,并对所有受试对象的ET-1基因中rs5370 (Lys198Asn)和rs2071942(G8002A)两个位点位进行基因分型及测序;同时,收集受试对象身高、体重、吸烟等资料。其中281例入选者皆为高血压初次确诊或已停用降压药2周以上,抽取静脉血后,给予口服硝苯地平控释片30 mg/d,共2周。分别按照收缩压及舒张压的降压效果,选取降压效果最好及最差的各50例病人,这样,共156例原发性高血压病人成为硝苯地平控释片降压疗效的研究对象。分别按收缩压和舒张压,对两极端组病人基因多态性与降压效果进行分析。第二部分：对确诊为高血压病的423例患者和114例健康志愿者空腹静脉抽血分别用于血脂、血糖及eNOS浓度等检测及全基因组的提取,并对所有受试对象的eNOS基因中T786C (rs2070744)和G894T (rs1799983)两个位点位进行基因分型及测序;同,收集受试对象身高、体重、吸烟等资料。其中281例入选者皆为高血压初次确诊或已停用降压药2周以上,抽取静脉血后,给予口服硝苯地平控释片30 mg/d,共2周。分别按照收缩压及舒张压的降压效果,选取降压效果最好及最差的各50例病人,这样,共156例原发性高血压病人成为硝苯地平控释片降压疗效的研究对象。分别按收缩压和舒张压,对两极端组病人基因多态性与降压效果进行分析。结果：第一部分：(1)两组患者中,除性别及年龄无差别外,高血压组患者的血脂、空腹血糖、血压及体重指数均明显高于健康对照组,两组有统计学差异(P0.01),此外高血压组患者吸烟人数明显高于健康对照组(P0.001)。(2)ET-1基因rs2071942和rs5370的多态性检测符合Hardy-Weinberg平衡(p0.05),表明所选取的受试对象来自检个较大的、处于随机分配平衡状态的群体,具有一定代表性。(3)高血压患者中,rs5370位点的纯合了G/G、T/T及杂合子G/T的基因型频率分别为73.0%、2.3%及24.7%,T等位基因频率为14.6%,但与健康对照组相比,无论在基因型频率还是等位基因频率均有统计学差异。 (4)高血压组rs2071942位点的G等位基因频率为66.6%,明显低于健康对照组的76%,两组差异明显,P值为0.007,表明A等位基因的频率增高可能与高血压的发病相关；以G/G与G/A+A/A进行比较,发现高血压组与对照组之间亦有显著的统计学差异(P=0.001),表明G/G型纯合子的个体可能能够抵抗高血压的发生(5)ET-1基因rs2071942和rs5370的基因型分布分布均与性别、血压无相关性。(6)无论以收缩压还是以舒张压来分,ET-1基因rs5370位点多态性与硝苯地平控释片降压效果的关系,均无显著相关性。(7)在高血压组及健康对照组内,超重者rs2071942基因型G/G频率有升高趋势,而携带A等位基因的基因型有下降趋势,但均无统计学意义(P=0.067和P=0.057)。(8)在高血压患者中rs5370位点携带T等位基因的基因型的吸烟者比例明显高于G/G纯合子患者,提示rs5370位点携带T等位基因的吸烟者可能与高血压有关。(9)高血压患者血清ET-1浓度与健康对照组相比有显著的统计学意义(P0.05)第二部分：(1)除性别及年龄无差别外,高血压组患者的血脂、空腹血糖、血压及体重指数均明显高于健康对照组,两组有统计学差异(P0.01),此外高血压组患者吸烟人数明显高于健康对照组(P0.001)。(2) eNOS基因T786C和G894T的多态性检测符合Hardy-Weinberg平衡(p0.05),表明所选取的受试对象来自一个较大的、处于随机分配平衡状态的群体,具有一定代表性。(3)eNOS基因启动子T786C位点T/T, T/C和C/C基因型在高血压组分别为22.22%,51.53%,26.47%,在健康对照组分别为37.72%,53.51%,8.77%,此位点高血压病组与健康对照组的基因分布频率差异有显著性。(4)eNOS基因第七外显子第894位点G/G, G/T和T/T基因型在高血压组分别为69.28%,22.46%,8.26%,在健康对照组分别为82.46%,14.91%,2.63%,此位点基因分布频率在高血压病组与对照组的差异有显著性。(5)当T786C、 G894T两位点基因型为CC+TT或TC+TT时,经计算患原发性高血压的OR值明显大于基因型为TT+GG者。(6)高血压患者血清eNOS浓度与健康对照组相比降低,有显著的统计学意义(P0.05),但无论高血压组还是健康对照组,组内不同eNOS G894T基因型间血浆eNOS浓度比较无显著差异(P0.05)。 (7)eNOS的G894T多态性与硝苯地平控释片降压效果,无论以收缩压还是以舒张压来分,均无显著相关性。结论：第一部分(1)高血压患者ET-1基因rs2071942的A等位基因频率明显增高,提示ET-1基因A等位基因也许可以作为江西汉族人群高血压易感基因的遗传标志;(2) ET-1rs5370多态性与硝苯地平控释片降压疗效无相关性；(3)高血压病的高危因素可能会影响ET-1基因多态性的改变;(4)rs5370位点携带有T等位基因的吸烟者可能更易患高血压。第二部分(1) eNOS基因启动子T786C及第七外显子第894位点基因多态性与原发性高血压的发病有一定程度的相关性；(2) eNOS基因启动子T786C位点T/T及第七外显子894位点G/G基因型是原发性高血压的保护性基因;(3) eNOS基因T786C和G894T变异在原发性高血压的发病中可能有一定程度的协同作用；(4)在江西汉族高血压人群中,,G894T多态性与血浆eNOS浓度无显著相关性；(5) eNOS G894T多态性与硝苯地平控释片降压疗效无相关性。
[Abstract]:Objective: essential hypertension (EH) is a chronic disease with multiple genetic and environmental interaction, and is an independent risk factor for coronary heart disease, cerebral cerebral vascular disease and end-stage renal disease. Many studies have confirmed that there is a susceptible gene for hypertension in the human basis. It has not been found that the polymorphism of a human gene is directly related to the occurrence of hypertension. Previous studies have shown that the increase in the expression of endothelin -1 (ET-1) can enhance the resistance of arterial blood vessels. The level of ET-1 in plasma of hypertensive patients is significantly higher than that of people with normal blood pressure, and the damage of target organs is more serious, suggesting that ET-1 may be more serious. The risk of hypertension is increased; in addition, the overexpression of the ET-1 receptor gene in the arterial wall of the hypertensive patients may be found, which may indicate that the mechanism of ET-1 induced hypertension is achieved through a method of affecting the energy barrier of endothelial function or promoting the proliferation of vascular smooth muscle cells; the use of the ET-1 receptor antagonist can be used. There is a significant correlation between ET-1 and hypertension. Previous studies have also shown that nitric oxide (NO) plays an important role in cardiovascular disease, and nitric oxide is produced under the catalysis of nitric oxide synthase (NOS). Three different nitric oxide synthases are in cardiovascular disease. The effects of the nitric oxide synthase will become a new strategy for the treatment of cardiovascular diseases. In view of the results suggested that ET-1, eNOS is associated with the occurrence of hypertension, the ET-1, eNOS gene has been considered as a high risk candidate for hypertension. The study of the relationship between genotyping and disease and the relationship with the antihypertensive effect is the basis for the early diagnosis, prevention and treatment of EH. This paper is divided into two chapters: the correlation of endothelin -1 gene polymorphism and the effect of primary hypertension and nifedipine in Jiangxi Han population. Two. The correlation method between the gene polymorphism of nitric oxide synthase and the effect of primary hypertension and nifedipine in Jiangxi Han population: Part 1: the detection of blood lipid, blood glucose and ET-1 concentration and the extraction of whole genome were used in 423 patients with essential hypertension and 114 healthy volunteers, respectively. The two loci of rs5370 (Lys198Asn) and rs2071942 (G8002A) in the ET-1 gene of the subjects were genotyping and sequencing. At the same time, the height, weight, smoking and other data of the subjects were collected. 281 of the subjects were all first diagnosed with hypertension or more than 2 weeks of antihypertensive drugs had been discontinued. After the extraction of venous blood, oral Nifedipine Controlled Release Tablets 30 was given. Mg/d for 2 weeks. According to the effect of systolic and diastolic blood pressure, 50 patients with the best and worst antihypertensive effect were selected, so that 156 patients with essential hypertension became the research object of the antihypertensive effect of Nifedipine Controlled Release Tablets. According to the systolic and diastolic pressure, the gene polymorphism and the effect of blood pressure in the two extremes were divided. The second part: 423 patients with essential hypertension and 114 healthy volunteers with fasting venous blood were used to detect the blood lipid, blood glucose and eNOS concentration and to extract the whole genome, and the gene typing and sequencing of the two loci of T786C (rs2070744) and G894T (rs1799983) in all the subjects of the subjects were sequenced and sequenced. 281 of the 281 patients were given the first diagnosis of hypertension or more than 2 weeks of antihypertensive drugs. After the extraction of venous blood, the oral Nifedipine Controlled Release Tablets was given 30 mg/d for 2 weeks. In accordance with the effect of systolic and diastolic blood pressure, the best and worst 50 patients were selected, respectively. A total of 156 patients with essential hypertension became the research object of the antihypertensive effect of Nifedipine Controlled Release Tablets. According to the systolic and diastolic pressure, the gene polymorphism and antihypertensive effect of the two extremist groups were analyzed. The first part: (1) among the two groups, the blood lipid and fasting blood sugar in the hypertensive group were not different except for the sex and age. The blood pressure and body mass index were significantly higher than those in the healthy control group (P0.01). In addition, the number of smokers in the two groups was significantly higher than that in the healthy control group (P0.001). (2) the polymorphism of ET-1 gene rs2071942 and rs5370 conformed to Hardy-Weinberg balance (P0.05), indicating that the selected subjects were from a larger test. (3) in hypertensive patients, the rs5370 locus was G/G, the genotype frequencies of T/T and heterozygote G/T were 73%, 2.3% and 24.7%, and the T allele frequencies were 14.6%, but there were statistically significant differences in genotype frequencies and allele frequencies compared with those of the healthy control group (4). The G allele frequency of rs2071942 loci in the hypertension group was 66.6%, which was significantly lower than that of the healthy control group, which was significantly lower than that in the healthy control group. The two groups were significantly different, and the P value was 0.007. The higher frequency of the A allele might be associated with the pathogenesis of hypertension. Compared with G/G and G/A+A/A, there were significant statistical differences between the hypertension group and the control group (P=0.001). The results showed that the individuals of G/G homozygote may be able to resist hypertension (5) ET-1 gene rs2071942 and rs5370 genotype distribution distribution were not related to sex and blood pressure. (6) no matter in systolic or diastolic pressure, there was no significant correlation between the rs5370 locus polymorphism of the ET-1 gene and the effect of Nifedipine Controlled Release Tablets's antihypertensive effect. (7) in the hypertension group and the healthy control group, the frequency of rs2071942 genotype G/G increased in the overweight people, but the genotype of A allele was decreased, but there was no statistical significance (P=0.067 and P=0.057). (8) the genotype of T allele carrying T allele in the hypertensive patients was significantly higher than that of G/G homozygote The smokers who suggest that the rs5370 locus carrying T allele may be related to hypertension. (9) the serum ET-1 concentration in hypertensive patients has significant statistical significance (P0.05) compared with the healthy control group (P0.05): (1) the blood lipid, fasting blood glucose, blood pressure and body mass index of the hypertensive patients are obviously Gao Yujian except for sex and age. In the control group, there was a statistical difference between the two groups (P0.01). In addition, the number of smokers in the hypertension group was significantly higher than that in the healthy control group (P0.001). (2) the polymorphism of eNOS gene T786C and G894T conformed to Hardy-Weinberg balance (P0.05), indicating that the selected subjects were from a larger group in a random distribution equilibrium state. (3) the T786C locus T/T of the eNOS gene promoter, T/C and C/C genotypes were 22.22%, 51.53%, 26.47% in the hypertension group, respectively 37.72%, 53.51%, 8.77% in the healthy control group. The gene distribution frequency difference between the hypertensive group and the healthy control group was significant. (4) the 894th loci of eNOS gene seventh exon G/G, G/T and T/T. The genotype in the hypertension group was 69.28%, 22.46%, 8.26%, respectively, 82.46%, 14.91%, 2.63% in the healthy control group. The difference in the frequency of gene distribution between the hypertensive group and the control group was significant. (5) when T786C, G894T two loci genotype was CC+TT or TC+TT, the OR value of the patients with essential hypertension was significantly greater than that of the genotype TT. (6) (6) the serum concentration of eNOS in patients with hypertension was lower than that of the healthy control group. There was significant statistical significance (P0.05), but there was no significant difference in the concentration of eNOS between the different eNOS G894T genotypes in the hypertensive group and the healthy control group (P0.05). (7) the G894T polymorphism of eNOS and the effect of Nifedipine Controlled Release Tablets on the antihypertensive effect, There is no significant correlation between the systolic pressure or diastolic pressure. Conclusion: the first part (1) the A allele frequency of ET-1 gene rs2071942 in hypertensive patients is significantly higher, suggesting that the A allele of the ET-1 gene may be a genetic marker for the susceptibility gene of hypertension in Jiangxi Han population; (2) ET-1rs5370 polymorphism and nifedipine controlled release (3) high risk factors of hypertension may affect the change of ET-1 gene polymorphism; (4) smokers with T allele in rs5370 loci may be more susceptible to hypertension. Second (1) eNOS gene promoter T786C and seven exon 894th loci gene polymorphisms are associated with the onset of essential hypertension The degree of correlation; (2) eNOS gene promoter T786C site T/T and seven exon 894 locus G/G genotype is a protective gene for essential hypertension; (3) the eNOS gene T786C and G894T variation may have a certain degree of synergy in the pathogenesis of essential hypertension; (4) the polymorphism of G894T in Jiangxi Han hypertension population There was no significant correlation with plasma eNOS concentration; (5) eNOS G894T polymorphism was not associated with Nifedipine Controlled Release Tablets hypotensive effect.

【学位授予单位】：南昌大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R544.1

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