IGF-1与IGF-1R基因多态性与原发性高血压遗传易感性的分子流行病学研究
发布时间：2018-08-05 10:25
【摘要】：目的:胰岛素样生长因子1(Insulin-like growth factor 1,IGF-1),是由70个氨基酸组成的碱性肽,因其结构与胰岛素有50%同源性而得名。通过与其受体(IGF-1 receptor,IGF-1R)结合发挥促进生长分化及类似胰岛素代谢作用。越来越多的研究指出IGF-1可能与心脑血管疾病的发生密切相关。最近的证据表明,IGF-1及受体被认为是导致血压升高的病理生理反应的重要介质。本研究的主要目的是评估IGF-1及IGF-1R基因遗传变异与血压变化及高血压的关系,探讨IGF-1及IGF-1R基因变异在高血压发病中的分子机制,为高血压临床预后评价提供敏感指标,并为筛选治疗药物靶点提供理论依据。方法:2009年在江苏省南部地区两个乡镇社区经整群抽样的方法纳入了年龄在35-75岁的的居民进行流行病学调查。血压测量和高血压标准参考《中国高血压防治指南》(2005修订版),最终纳入高血压病例2012例,对照2210例。并在2014年5月到2016年1月对人群进行随访,收集随访期间发生高血压的结局事件。将成人研究中发现的与高血压显著关联位点进一步在该地区3551名儿童人群中进行验证。并在成人中选取137例高血压病例,159例健康对照探讨外周IGF-1及IGF-1R蛋白水平与原发性高血压之间的关系。采用连锁不平衡分析和生物信息学功能预测相结合的方法,选择了IGF-1和IGF-1R上各五个标签单核苷酸多态性(target Single Nucleotide Polymorphisms,tag SNPs),并应用Taq Man技术进行基因分型。计量资料和计数资料分别采用两样本t检验和卡方检验比较病例组和对照组间临床特征和基因型分布的差异。采用Logistic回归模型评估病例对照中IGF-1及IGF-1R基因多态性和高血压的关联,并用Cox比例风险回归模型分析基因变异对高血压发生的风险比。采用一般线性模型GLM分析血压数量性状之间的关系。HAPSTATA 3.0进行单倍型分析,评估单体域的多个位点对高血压的影响。结果:病例对照研究中,IGF-1和IGF-1R基因遗传变异与高血压关联分析显示,校正年龄、性别、TC、TG、HDL-C、LDL-C、GLU、BMI、吸烟和饮酒等混杂因素后,IGF-1R基因的rs1815009和rs2654981与原发性高血压存在显著关联,OR(95%CI)分别为0.905(0.831-0.986)和1.193(1.014-1.405)。进一步分层分析发现,IGF-1基因rs35767的变异在正常体重人群中是高血压的保护因素,而在肥胖人群中是高血压的危险因素,OR(95%CI)分别为0.833(0.724-0.958)和1.345(1.021-1.773)。IGF-1R基因的rs2229765在55岁人群、不饮酒人群和超重人群中以及rs2002880在饮酒和超重人群中与原发性高血压有统计学关联(P0.05)。血压数量性状分析显示在服用抗高血压药物组中rs6218、rs5742612和rs13379905不同基因型携带者之间的血压水平有差异。单体型分析显示,rs1815009和rs2654981位于同一Block。和常见单体型G-A相比,单体型A-A和高血压存在显著关联,校正OR(95%CI)为1.19(1.02-1.39),P=0.03。前瞻性随访发现,校正年龄、性别、TC、TG、LDL-C、HDL-C、糖尿病、BMI、吸烟和饮酒混杂因素后,IGF-1R基因rs13379905的变异显著增加高血压的发病风险,其不同基因型CC、CT、TT携带者的发病密度分别为6654.95、7755.36和8566.04(/10万人年),并且该关联在非饮酒组和有高血压家族人群中更显著,HR(95%CI)分别为1.357(1.080-1.707)和2.100(1.381-3.194),P分别为0.009、0.001。IGF-1基因rs6219位点CT突变在55岁年龄组、肥胖和有高血压家族史人群中显著降低高血压的发病风险,在肥胖人群中rs2002880的AA基因型携带者相比GG基因型携带者降低高血压的发病风险(P0.05)。儿童人群分析结果显示,校正年龄、性别、BMI、TC、TG、HDL-C和LDL-C后,在男性儿童中rs13379905位点CT变异与高血压前期以及高血压前期合并高血压呈正关联,OR(95%CI)分别为1.795(1.191-2.703),P=0.005;1.583(1.148-2.184),P=0.005。而在女性儿童中该位点变异与高血压前期呈负关联,相加和显性模型的OR(95%CI)分别为0.525(0.295-0.932),P=0.028;0.529(0.293-0.956),P=0.035。在男性儿童中,rs13379905不同基因型(CC、CT、TT)的SBP的Z评分分别为1.04±0.97、1.09±1.03、1.89±0.66,呈线性增加趋势,P=0.042。血清IGF-1和IGF-1R水平在高血压组和对照组之间的差异无统计学意义(P0.05),rs2002880位点GA基因型携带者血清IGF-1R水平高于GG携带者,P=0.011。结论:研究结果显示IGF-1R基因多个位点变异与成人高血压的发病存在关联,且rs13379905与男性儿童高血压显著关联。年龄、BMI和家族史对IGF-1基因变异与高血压的关联效应具有修饰作用。这些结果均表明,IGF-1信号通路的遗传变异可能影响高血压的遗传易感性。
[Abstract]:Objective: insulin like growth factor 1 (Insulin-like growth factor 1, IGF-1), a basic peptide composed of 70 amino acids, is named after its structure is 50% homologous with insulin. By combining its receptor (IGF-1 receptor, IGF-1R) to promote growth and differentiation and similar insulin metabolism. More and more studies suggest that IGF-1 may be possible. Recent evidence suggests that IGF-1 and its receptors are important mediators of the pathophysiological response to elevated blood pressure. The main purpose of this study is to assess the relationship between genetic variations of IGF-1 and IGF-1R genes and blood pressure changes and hypertension, and to explore the incidence of IGF-1 and IGF-1R gene mutations in the pathogenesis of hypertension. The molecular mechanism in this study provides a sensitive indicator for the evaluation of the clinical prognosis of hypertension and provides a theoretical basis for screening drug targets. Methods: in 2009, two townships in the southern part of Jiangsu province were enrolled in the epidemiological survey of residents aged 35-75 years by cluster sampling. China's guidelines for the prevention and control of hypertension (2005 revised edition) were included in 2012 cases of hypertension and 2210 cases of control. The population was followed up from May 2014 to January 2016 to collect the outcome of hypertension during the follow-up period. The significant correlation site with hypertension found in the adult study was further developed in 3551 children in the region. 137 cases of hypertension were selected and 159 healthy controls were used to investigate the relationship between peripheral IGF-1 and IGF-1R protein levels and essential hypertension. A combination of linkage disequilibrium analysis and bioinformatics functional prediction was used to select five label single nucleotide polymorphisms (target Single) on IGF-1 and IGF-1R Nucleotide Polymorphisms, tag SNPs), and using Taq Man technology to genotyping. Measurement data and counting data were compared with two samples t test and chi square test to compare the difference of clinical characteristics and genotype distribution between the case group and the control group. The Logistic regression model was used to evaluate the polymorphism and high of the IGF-1 and IGF-1R genes in the case control. The correlation of blood pressure and the Cox proportional risk regression model were used to analyze the risk ratio of genetic variation on the occurrence of hypertension. A haplotype analysis was carried out by the general linear model GLM analysis of the quantitative characters of blood pressure,.HAPSTATA 3, to assess the effect of multiple loci in the mono domain on hypertension. Results: in a case-control study, IGF-1 and IGF-1R based The correlation analysis between genetic variation and hypertension showed that after correction of age, sex, TC, TG, HDL-C, LDL-C, GLU, BMI, smoking and drinking, there was a significant association between the rs1815009 and rs2654981 of the IGF-1R gene and essential hypertension, and OR (95%CI) was 0.905 (0.831-0.986) and 1.193. The variation of rs35767 is a protective factor for hypertension in normal weight population, and the risk factor for hypertension in obese people. The rs2229765 of OR (95%CI) is 0.833 (0.724-0.958) and 1.345 (1.021-1.773).IGF-1R gene rs2229765 in 55 year old people, non drinkers and overweight people, and rs2002880 in drinking and overweight people. The blood pressure quantitative trait analysis (P0.05). The blood pressure quantitative trait analysis showed that the blood pressure levels were different among the rs6218, rs5742612 and rs13379905 carriers in the antihypertensive group. The haplotype analysis showed that rs1815009 and rs2654981 were in the same Block. and the common haplotype G-A, haplotype A-A and hypertension. There was a significant correlation, corrected OR (95%CI) 1.19 (1.02-1.39), P=0.03. prospective follow-up found that correction of age, sex, TC, TG, LDL-C, HDL-C, diabetes, BMI, smoking and alcohol confounding, IGF-1R gene rs13379905 variation significantly increased the risk of hypertension, and the incidence of different genotypes was 6654.95, respectively. 7755.36 and 8566.04 (/10 million years), and the association was more significant among non drinking and hypertensive families, and HR (95%CI) was 1.357 (1.080-1.707) and 2.100 (1.381-3.194) respectively. P was the CT mutation of the 0.009,0.001.IGF-1 gene rs6219 site in the 55 year old group, and the obesity and hypertension family history significantly reduced the incidence of hypertension. The risk of disease, in obese people, rs2002880 AA genotype carriers lower the risk of hypertension than GG genotype carriers (P0.05). Children population analysis showed that correction of age, sex, BMI, TC, TG, HDL-C, and LDL-C, CT variation in rs13379905 sites in male children with prehypertension and prehypertension combined with hypertension OR (95%CI) was 1.795 (1.191-2.703), P=0.005; 1.583 (1.148-2.184), P=0.005., and the mutation of this locus was negatively correlated with prehypertension in female children, and OR (0.295-0.932) (0.295-0.932), P=0.028; 0.529 (0.293-0.956) of the additive and dominant models respectively. The Z score of SBP in TT was 1.04 + 0.97,1.09 + 1.03,1.89 + 0.66, showing a linear trend. There was no significant difference between the serum IGF-1 and IGF-1R level of P=0.042. in the hypertension group and the control group (P0.05), and the rs2002880 locus GA genotype carrier was higher than that of the carrier. Multiple locus variations are associated with the incidence of hypertension in adults, and rs13379905 is significantly associated with hypertension in male children. Age, BMI and family history have modified the association effect of IGF-1 gene variation with hypertension. These results suggest that genetic variation in the IGF-1 signaling pathway may affect the genetic susceptibility to hypertension.
【学位授予单位】：皖南医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R544.11
本文编号：2165510
[Abstract]:Objective: insulin like growth factor 1 (Insulin-like growth factor 1, IGF-1), a basic peptide composed of 70 amino acids, is named after its structure is 50% homologous with insulin. By combining its receptor (IGF-1 receptor, IGF-1R) to promote growth and differentiation and similar insulin metabolism. More and more studies suggest that IGF-1 may be possible. Recent evidence suggests that IGF-1 and its receptors are important mediators of the pathophysiological response to elevated blood pressure. The main purpose of this study is to assess the relationship between genetic variations of IGF-1 and IGF-1R genes and blood pressure changes and hypertension, and to explore the incidence of IGF-1 and IGF-1R gene mutations in the pathogenesis of hypertension. The molecular mechanism in this study provides a sensitive indicator for the evaluation of the clinical prognosis of hypertension and provides a theoretical basis for screening drug targets. Methods: in 2009, two townships in the southern part of Jiangsu province were enrolled in the epidemiological survey of residents aged 35-75 years by cluster sampling. China's guidelines for the prevention and control of hypertension (2005 revised edition) were included in 2012 cases of hypertension and 2210 cases of control. The population was followed up from May 2014 to January 2016 to collect the outcome of hypertension during the follow-up period. The significant correlation site with hypertension found in the adult study was further developed in 3551 children in the region. 137 cases of hypertension were selected and 159 healthy controls were used to investigate the relationship between peripheral IGF-1 and IGF-1R protein levels and essential hypertension. A combination of linkage disequilibrium analysis and bioinformatics functional prediction was used to select five label single nucleotide polymorphisms (target Single) on IGF-1 and IGF-1R Nucleotide Polymorphisms, tag SNPs), and using Taq Man technology to genotyping. Measurement data and counting data were compared with two samples t test and chi square test to compare the difference of clinical characteristics and genotype distribution between the case group and the control group. The Logistic regression model was used to evaluate the polymorphism and high of the IGF-1 and IGF-1R genes in the case control. The correlation of blood pressure and the Cox proportional risk regression model were used to analyze the risk ratio of genetic variation on the occurrence of hypertension. A haplotype analysis was carried out by the general linear model GLM analysis of the quantitative characters of blood pressure,.HAPSTATA 3, to assess the effect of multiple loci in the mono domain on hypertension. Results: in a case-control study, IGF-1 and IGF-1R based The correlation analysis between genetic variation and hypertension showed that after correction of age, sex, TC, TG, HDL-C, LDL-C, GLU, BMI, smoking and drinking, there was a significant association between the rs1815009 and rs2654981 of the IGF-1R gene and essential hypertension, and OR (95%CI) was 0.905 (0.831-0.986) and 1.193. The variation of rs35767 is a protective factor for hypertension in normal weight population, and the risk factor for hypertension in obese people. The rs2229765 of OR (95%CI) is 0.833 (0.724-0.958) and 1.345 (1.021-1.773).IGF-1R gene rs2229765 in 55 year old people, non drinkers and overweight people, and rs2002880 in drinking and overweight people. The blood pressure quantitative trait analysis (P0.05). The blood pressure quantitative trait analysis showed that the blood pressure levels were different among the rs6218, rs5742612 and rs13379905 carriers in the antihypertensive group. The haplotype analysis showed that rs1815009 and rs2654981 were in the same Block. and the common haplotype G-A, haplotype A-A and hypertension. There was a significant correlation, corrected OR (95%CI) 1.19 (1.02-1.39), P=0.03. prospective follow-up found that correction of age, sex, TC, TG, LDL-C, HDL-C, diabetes, BMI, smoking and alcohol confounding, IGF-1R gene rs13379905 variation significantly increased the risk of hypertension, and the incidence of different genotypes was 6654.95, respectively. 7755.36 and 8566.04 (/10 million years), and the association was more significant among non drinking and hypertensive families, and HR (95%CI) was 1.357 (1.080-1.707) and 2.100 (1.381-3.194) respectively. P was the CT mutation of the 0.009,0.001.IGF-1 gene rs6219 site in the 55 year old group, and the obesity and hypertension family history significantly reduced the incidence of hypertension. The risk of disease, in obese people, rs2002880 AA genotype carriers lower the risk of hypertension than GG genotype carriers (P0.05). Children population analysis showed that correction of age, sex, BMI, TC, TG, HDL-C, and LDL-C, CT variation in rs13379905 sites in male children with prehypertension and prehypertension combined with hypertension OR (95%CI) was 1.795 (1.191-2.703), P=0.005; 1.583 (1.148-2.184), P=0.005., and the mutation of this locus was negatively correlated with prehypertension in female children, and OR (0.295-0.932) (0.295-0.932), P=0.028; 0.529 (0.293-0.956) of the additive and dominant models respectively. The Z score of SBP in TT was 1.04 + 0.97,1.09 + 1.03,1.89 + 0.66, showing a linear trend. There was no significant difference between the serum IGF-1 and IGF-1R level of P=0.042. in the hypertension group and the control group (P0.05), and the rs2002880 locus GA genotype carrier was higher than that of the carrier. Multiple locus variations are associated with the incidence of hypertension in adults, and rs13379905 is significantly associated with hypertension in male children. Age, BMI and family history have modified the association effect of IGF-1 gene variation with hypertension. These results suggest that genetic variation in the IGF-1 signaling pathway may affect the genetic susceptibility to hypertension.
【学位授予单位】：皖南医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R544.11
【参考文献】
相关期刊论文 前3条
1 陈伟伟;高润霖;刘力生;朱曼璐;王文;王拥军;吴兆苏;李惠君;顾东风;杨跃进;郑哲;蒋立新;胡盛寿;;《中国心血管病报告2015》概要[J];中国循环杂志;2016年06期
2 刘力生;;中国高血压防治指南2010[J];中华高血压杂志;2011年08期
3 唐强;刘海玲;刘昭前;;抗高血压药物的基因组学研究进展[J];中南药学;2007年02期
相关博士学位论文 前1条
1 韩胜红;GH-IGF-I轴基因多态性及环境因素与缺血性脑卒中的分子流行病学研究[D];华中科技大学;2009年
，本文编号：2165510
本文链接：https://www.wllwen.com/yixuelunwen/xxg/2165510.html
最近更新
教材专著
