| Objective:The essential hypertension (EH) is based on the interaction between polygenes hereditary and environmental factors. It is also an independent risk factor of cardiovascular diseases, stroke, and the end stage of kidney dysfuction. A vast amount of researches have been conducted to identify susceptibility loci in humans of hypertension. Nonetheless, no genetic polymorphism has been identified to show consistent association with hypertension in humans. Previous studies have demonstrated that endothelin-1 (ET-I) expression has been linked to resistance artery remodeling, as well as ET-1 plasma level was higher in patients with EH than in normal blood pressure person and paralleled the severity of target organ damage, suggesting that it may increase the risk of hypertension. The ET receptor gene was also found to be overexpressed in the arteries of hypertensive patients, which suggests that ET-1 contributes to the pathogenesis of hypertension by endothelial dysfunction or proliferation of vascular smooth muscle cells. Further support for the association between ET-1 and hypertension comes from a study demonstrated that treatment with an ET-1 receptor antagonist for chronic hypertensive patients reduced blood pressure. Previous studies also have demonstrated that Nitric oxide (NO) plays an important role in cardiovascular system. Nitric oxide synthase is the key enzyme during the synthesis process of nitric oxide. Different nitric oxide syntheses (NOS) have different effects on cardiovascular disease. Therefore, the ET-1, eNOS gene has been proposed as a candidate risk factor for hypertension. It is the foundation of early diagnosis, prevention and treatment of essential hypertension that screening related gene’s single nucleotide polymorphism (SNPs) polymorphism of essential hypertension and investing the relationship of gene and the effect of anti-hypertension drugs. The present study is to examine the effect of polymorphisms of ET-1 and eNOS on the risk of hypertension and antihypertensive effect of nifedipine.Methods:Part Ⅰ:423 hypertensive patients and 114 healthy voluntary were recruited into this study. Two SNPs in EDN1, one is rs5370 (Lys198Asn) and another is rs2071942 (G8002A), for G allele replaced by A allele, and two SNPs in eNOS, one is the T786C (rs2070744) and another is the G894T (rs 1799983),had been genotyped in all participants. Some clinical dataes and survey of life habits were also evaluated. A total of 281 essential hypertensive subjects were treated with nifedipine 30 mg/d for 14 consecutive days. Based on their blood pressure response to nifedipine, a total of 156 subjects were divided into two categories:they were either in the top 50 subjects whose systolic blood pressure (SBP) or diastolic blood pressure (DBP) best respond to nifedipine or on the bottom 50 subjects whose SBP or DBP showed the worst response to nifedipine.Results:PartⅠ:(1) The distribution of sex and lifestyle factors, as well as several quantitative variables (age, BMI, TC, LDL-C, FBS, SBP, DBP) in healthy controls and hypertension patients are evaluated. Except for sex distribution and age, all variables were significantly different between hypertension and control groups (P<0.01). The proportion of incident cases of hypertension was larger among smokers than non-smokers (P<0.001). (2)Polymorphisms rs2071942 and rs5370 of ET-1 gene have been tested in Hardy-Weinberg equilibrium (p>0.05). (3) The genotype frequencies of rs5370 in hypertension patients were 73.0%(G/G),2.3%(T/T), 24.7%(G/T), respectively, and T allele frequency was 14.6%; But none of them was observed statistically significant when compared with healthy controls. (4) For rs2071942, G allele frequency (66.6%) in hypertension patients was significantly lower than controls (76%) (P=0.007), as well as the distributions of frequency of G/G and G/A+A/A were different between two groups (P=0.001), which suggested the increases of A allele frequency may be associated with the pathogenesis of hypertension. (5) The distributions of genotype frequency of those two SNPs seemed to be no association with gender and blood pressure in all subjects or in hypertension patients. (6)The ET-1 rs5370 polymorphism is not a significant factor in the antihypertensive effect of nifedipine. (7) the A allele carrying genotypes of rs2071942 were less frequent in overweight subjects than in normal ones, but the difference was not statistically significant (P=0.067, P=0.057, respectively). (8) The proportion of smokers in hypertensive subjects which carrying the T allele genotypers of rs5370 was significantly higher than those G/G homozygous patients, suggesting that smokers containing T allele may be associated with hypertension. (9) Plasma ET concentration in hypertensive subjects was significantly higher than controls (P<0.05).Part Ⅱ:(1) Polymorphisms T786C, G894T of eNOS gene have been tested in Hardy-Weinberg equilibrium (p>0.05). (2) eNOS promoter region T786C, the frequencies of TT, TC and CC genotype were 22.22%,51.53%, and 26.47% in hypertensive patients and 37.72%,53.51% and 8.77% in controls. A significant difference was seen in the distribution frequency in the two groups of hypertensive patients and controls. (3) The 894th site of the seventh extron of eNOS the frequencies of GG, GT and TT genotype were 69.28%,22.46% and 8.26% in hypertensive patients and 82.46%,14.91% and 2.63% in healthy controls. A significant difference was also seen in the two groups. (4) When the genotypes of the two sites were CC and TT or TC and TT the OR of morbility of essential hypertension were much higher than TT and GG. (5) Plasma eNOS concentration in hypertensive subjects was significantly lower than healthy controls (P<0.05). (6) The eNOS G894T polymorphism is not a significant factor in the antihypertensive effect of Nifedipine.Conclusions:Part Ⅰ:(1) rs2071942 A allele might be a marker for hypertension occurrence in Jiangxi population;(2) In this hypertensive population study, there is no significant association of the rs5370 polymorphism of ET-1 with the antihypertensive effect of nifedipine.(3) High risk factors of hypertension may affect the changes of ET-1 gene polymorphism;(4) Smokers carrying T allele genotype of rs5370 may be more susceptible to hypertension in Jiangxi Province;Part Ⅱ:(1) Polymorphisms of the promoter region T786C and 894th site G/T of eNOS gene have something to do with morbility of EH;(2) Genotypes TT of the promoter region T786C and GG of 894th site of eNOS gene may have some protective effect on EH;(3) There are some interaction between polymorphisms of the two sites which we studied;(4) In this study of hypertensive population, there is no significant association of the G894T polymorphism with plasma eNOS concentration;(5) In this study of hypertensive population, there is no significant association of the G894T polymorphism of eNOS with the antihypertensive effect of nifedipine. |
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