老年原发性高血压左室重构与环境因素及HLA-DRB1 SNPs相关性研究
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摘要
原发性高血压(EH)是危害人类健康的主要心血管疾病,是一种多基因遗传病。心脏是其最常见的靶器官损伤之一,主要表现为左室肥厚(LVH)和左室扩张(LVD)。EH患者中约有1/3会出现LVH,而LVH又是心衰、冠心病、脑卒中、心律失常、猝死及心血管疾病死亡率和致死率的独立危险因素。心血管风险评估除考虑LVH外,LVD不容忽视。EH左室重构发病机制仍未完全明了,其危险因素证据仍有待积累。EH是“基因-基因”与“基因-环境”相互作用的结果,属于多基因多因素遗传疾病。EH相关性左室重构的易感基因及其多态性尚不清楚。HLA抗原作为人类最高多态性的遗传系统,与疾病的免疫、遗传易感性直接相关,因而EH与HLA基因的相关性研究是高血压免疫遗传领域的一个热点。国内外许多血清学、基因学研究和连锁分析均显示,HLA抗原特异性或等位基因与EH及左室重构的易感性存在关联,但存在种族差异。
本研究通过对HLA-DRB1的三个SNPs位点与老年EH左室重构相关性研究,探讨HLA-DRB1单核苷酸多态性与EH左室重构的关联;为老年EH左室重构机制及防治等提供分子生物学理论依据。研究发现HLA-DRB1 rs2308765可能是老年EH左室重构的危险因素;年龄可能是老年人LVD的危险因素;年龄、腹围可能是老年LVH的危险因素。
Background: left ventricular remodeling is a major kind of target organ damage of essential hepertension(EH), mainly for left ventricular hypertrophy(LVH) and Left Ventricular dilation (LVD). In hypertensives, the prevalence of LVH is about one third. LVH is an independent risk factor and predictor of congestive heart failure, coronary heart disease, stroke, arhythmia, sudden cardiac death, cardiovascular (CV) events and all-cause mortality. Regression of echocardiographic left ventricular hypertrophy after corresponding therapy lowers risk of coronary heart disease in hypertensives.But the degree of EH-LVH does not parallel the level of blood Pressure,the course of hypertension,or reversal level of hypertensive LVH by pharmacological treatments. Left ventricular remodeling serious impacts on cardiac systolic and diastolic function.Current studies believed that except of haemodynamic factors, there still more than 50% of the variances of left ventricular mass were insoluble. Several non-haemodynamic factors have been discussed playing a role in the process of myocardial hypertrophy, including age, sex, genetic factors and so on. The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans.MHC are some of the most genetically variable coding loci in human.Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies.As early as 1989, Dubov and his colleagues had begun to study the association between HLA and LVH.They found the patients with associated hypertrophic cardiomyopathy and asymmetric hypertrophy of the myocardium showed the high rate of DR1 and DR4 antigen demonstration. Then, Emmanuel J、Vlachonikolis IG,et al considered HLA-DR11 was associated with LVH,but this association was significant only in the groupⅢwith Grade 2 or 3 hypertension. In conclusion,certain HLA phenotypes may be related to the levels of arterial blood pressure.HLA-DQ7 and DR17 were associated with vascular wall hypertrophy in hypertensives but not in normotensive individuals. Moreover, this association was independent not only of the blood pressure levels, but also of the serum lipid concentrations.However, the distribution of HLA has obvious racial, ethnic, geographic differences, resulting in LVH associated with different HLA antigen types. Even people with the same race, in the same region also have differences.Objectives: The objective of this study was to investigate the association between human leukocyte antigens single nucleotide polymorphisms (HLA-SNPs) and left ventricular remodeling,as expressed by left entricular mass (LVM) and left ventricular dialation(LVD), in elderly hypertensives;and also to study the other risk factors of left ventricular remodeling. Methods: We examined 148 elderly subjects with EH. According to three kinds of different standards, the population was classified into different groups: hypertensives with or without LVH (EH-LVH+ or EH-LVH-); hypertensives with or without LVD (EH-LVD+ or EH-LVD-); group1 (LVM/h≤110g/m), group2 (LVM/h 110~150g/m), group3 (LVM/h>150g/m). Three SNPs of HLA-DRB1 were genotyped by multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR): rs2308765, rs9269186, rs3135388 included. LVH, LVM/h and LVD were determined by ultrasonography.All subjects were examined stature,body mass,waist circumference (WL), abdominal circumference(AC), fasting blood glucose(FPG), total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and serum creatinine and so on. All statistical analyses were carried out by using SAS for windows. The Hardy-Weinberg (H-W) equilibrium was tested for genetype and allele frequencies distributions of SNPS by goodness-of-fit chi-square test. Results:1. rs2308765 displays G/T and G/G, rs3135388 displayed C/T and T/T. rs9269186 had three kinds of phenotypes: C/G,C/C and G/G. rs9269186 was not in accordance with H-W equilibrium in EH-LVH- group, rs3135388 wasn’t in accordance with H-W equilibrium in EH-LVD- group. other gene polymorphisms were all in accordance with H-W equilibrium.2.①Single factor analysis and Logistic analysis revealed that none of the environmental factors above showed significantly difference between EH-LVH- and E-LVH+ groups (P>0.05).②Single factor analysis showed that EH-LVD+ group was accompanied with significantly higher WL and AC than EH-LVH- group (P<0.05). Then Logistic analysis found rs2308765 and age were significantly differences between EH-LVD+ and EH-LVD- group(P<0.05), and they were risk factors of LVD (OR>1).③body mass index, AC and WL showed significant differences between LVM/h groups(P>0.05); sex, age and AC associated with LVM/h,OR in order were 0.165, 1.640, 3.627, and the 95% confidence interval(CI) of OR didn’t include 1. 3.None of the three SNPs show significant difference between the EH-LVH- group and E-LVH+groups(P>0.05). rs2308765’genotype and allele frequencies show significant differences between EH-LVD- and EH-LVD+ groups(P<0.05, OR>1, 95%CI didn’t included 1). The analysis of Loci chosen for hap-analysis: rs2308765, rs9269186, rs3135388 show that TCC alleles combination were significantly differences between EH-LVH- and EH-LVH+ groups (P=0.032, OR=4.590, 95%CI=[1.002~21.030]); while GCC and TCC alleles combination were significant differences between EH-LVD- and EH-LVD+ groups (P<0.01). OR of GCC alleles combination is 0.277,OR of TCC alleles combination is 8.299, their 95%CI both didn’t included 1. Conclusion: (1) In elderly patients, Age may be risk factors of LVD; age and AC may be risk factors of LVH. (2) HLA-DRB1 rs2308765 SNPs may be risk factor of elderly EH associated left ventricular remodeling.
本研究通过对HLA-DRB1的三个SNPs位点与老年EH左室重构相关性研究,探讨HLA-DRB1单核苷酸多态性与EH左室重构的关联;为老年EH左室重构机制及防治等提供分子生物学理论依据。研究发现HLA-DRB1 rs2308765可能是老年EH左室重构的危险因素;年龄可能是老年人LVD的危险因素;年龄、腹围可能是老年LVH的危险因素。
Background: left ventricular remodeling is a major kind of target organ damage of essential hepertension(EH), mainly for left ventricular hypertrophy(LVH) and Left Ventricular dilation (LVD). In hypertensives, the prevalence of LVH is about one third. LVH is an independent risk factor and predictor of congestive heart failure, coronary heart disease, stroke, arhythmia, sudden cardiac death, cardiovascular (CV) events and all-cause mortality. Regression of echocardiographic left ventricular hypertrophy after corresponding therapy lowers risk of coronary heart disease in hypertensives.But the degree of EH-LVH does not parallel the level of blood Pressure,the course of hypertension,or reversal level of hypertensive LVH by pharmacological treatments. Left ventricular remodeling serious impacts on cardiac systolic and diastolic function.Current studies believed that except of haemodynamic factors, there still more than 50% of the variances of left ventricular mass were insoluble. Several non-haemodynamic factors have been discussed playing a role in the process of myocardial hypertrophy, including age, sex, genetic factors and so on. The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans.MHC are some of the most genetically variable coding loci in human.Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies.As early as 1989, Dubov and his colleagues had begun to study the association between HLA and LVH.They found the patients with associated hypertrophic cardiomyopathy and asymmetric hypertrophy of the myocardium showed the high rate of DR1 and DR4 antigen demonstration. Then, Emmanuel J、Vlachonikolis IG,et al considered HLA-DR11 was associated with LVH,but this association was significant only in the groupⅢwith Grade 2 or 3 hypertension. In conclusion,certain HLA phenotypes may be related to the levels of arterial blood pressure.HLA-DQ7 and DR17 were associated with vascular wall hypertrophy in hypertensives but not in normotensive individuals. Moreover, this association was independent not only of the blood pressure levels, but also of the serum lipid concentrations.However, the distribution of HLA has obvious racial, ethnic, geographic differences, resulting in LVH associated with different HLA antigen types. Even people with the same race, in the same region also have differences.Objectives: The objective of this study was to investigate the association between human leukocyte antigens single nucleotide polymorphisms (HLA-SNPs) and left ventricular remodeling,as expressed by left entricular mass (LVM) and left ventricular dialation(LVD), in elderly hypertensives;and also to study the other risk factors of left ventricular remodeling. Methods: We examined 148 elderly subjects with EH. According to three kinds of different standards, the population was classified into different groups: hypertensives with or without LVH (EH-LVH+ or EH-LVH-); hypertensives with or without LVD (EH-LVD+ or EH-LVD-); group1 (LVM/h≤110g/m), group2 (LVM/h 110~150g/m), group3 (LVM/h>150g/m). Three SNPs of HLA-DRB1 were genotyped by multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR): rs2308765, rs9269186, rs3135388 included. LVH, LVM/h and LVD were determined by ultrasonography.All subjects were examined stature,body mass,waist circumference (WL), abdominal circumference(AC), fasting blood glucose(FPG), total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and serum creatinine and so on. All statistical analyses were carried out by using SAS for windows. The Hardy-Weinberg (H-W) equilibrium was tested for genetype and allele frequencies distributions of SNPS by goodness-of-fit chi-square test. Results:1. rs2308765 displays G/T and G/G, rs3135388 displayed C/T and T/T. rs9269186 had three kinds of phenotypes: C/G,C/C and G/G. rs9269186 was not in accordance with H-W equilibrium in EH-LVH- group, rs3135388 wasn’t in accordance with H-W equilibrium in EH-LVD- group. other gene polymorphisms were all in accordance with H-W equilibrium.2.①Single factor analysis and Logistic analysis revealed that none of the environmental factors above showed significantly difference between EH-LVH- and E-LVH+ groups (P>0.05).②Single factor analysis showed that EH-LVD+ group was accompanied with significantly higher WL and AC than EH-LVH- group (P<0.05). Then Logistic analysis found rs2308765 and age were significantly differences between EH-LVD+ and EH-LVD- group(P<0.05), and they were risk factors of LVD (OR>1).③body mass index, AC and WL showed significant differences between LVM/h groups(P>0.05); sex, age and AC associated with LVM/h,OR in order were 0.165, 1.640, 3.627, and the 95% confidence interval(CI) of OR didn’t include 1. 3.None of the three SNPs show significant difference between the EH-LVH- group and E-LVH+groups(P>0.05). rs2308765’genotype and allele frequencies show significant differences between EH-LVD- and EH-LVD+ groups(P<0.05, OR>1, 95%CI didn’t included 1). The analysis of Loci chosen for hap-analysis: rs2308765, rs9269186, rs3135388 show that TCC alleles combination were significantly differences between EH-LVH- and EH-LVH+ groups (P=0.032, OR=4.590, 95%CI=[1.002~21.030]); while GCC and TCC alleles combination were significant differences between EH-LVD- and EH-LVD+ groups (P<0.01). OR of GCC alleles combination is 0.277,OR of TCC alleles combination is 8.299, their 95%CI both didn’t included 1. Conclusion: (1) In elderly patients, Age may be risk factors of LVD; age and AC may be risk factors of LVH. (2) HLA-DRB1 rs2308765 SNPs may be risk factor of elderly EH associated left ventricular remodeling.
引文
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