IGF-1與IGF-1R基因多態(tài)性與原發(fā)性高血壓遺傳易感性的分子流行病學(xué)研究
發(fā)布時(shí)間：2018-08-05 10:25
【摘要】：目的:胰島素樣生長(zhǎng)因子1(Insulin-like growth factor 1,IGF-1),是由70個(gè)氨基酸組成的堿性肽,因其結(jié)構(gòu)與胰島素有50%同源性而得名。通過(guò)與其受體(IGF-1 receptor,IGF-1R)結(jié)合發(fā)揮促進(jìn)生長(zhǎng)分化及類(lèi)似胰島素代謝作用。越來(lái)越多的研究指出IGF-1可能與心腦血管疾病的發(fā)生密切相關(guān)。最近的證據(jù)表明,IGF-1及受體被認(rèn)為是導(dǎo)致血壓升高的病理生理反應(yīng)的重要介質(zhì)。本研究的主要目的是評(píng)估IGF-1及IGF-1R基因遺傳變異與血壓變化及高血壓的關(guān)系,探討IGF-1及IGF-1R基因變異在高血壓發(fā)病中的分子機(jī)制,為高血壓臨床預(yù)后評(píng)價(jià)提供敏感指標(biāo),并為篩選治療藥物靶點(diǎn)提供理論依據(jù)。方法:2009年在江蘇省南部地區(qū)兩個(gè)鄉(xiāng)鎮(zhèn)社區(qū)經(jīng)整群抽樣的方法納入了年齡在35-75歲的的居民進(jìn)行流行病學(xué)調(diào)查。血壓測(cè)量和高血壓標(biāo)準(zhǔn)參考《中國(guó)高血壓防治指南》(2005修訂版),最終納入高血壓病例2012例,對(duì)照2210例。并在2014年5月到2016年1月對(duì)人群進(jìn)行隨訪(fǎng),收集隨訪(fǎng)期間發(fā)生高血壓的結(jié)局事件。將成人研究中發(fā)現(xiàn)的與高血壓顯著關(guān)聯(lián)位點(diǎn)進(jìn)一步在該地區(qū)3551名兒童人群中進(jìn)行驗(yàn)證。并在成人中選取137例高血壓病例,159例健康對(duì)照探討外周IGF-1及IGF-1R蛋白水平與原發(fā)性高血壓之間的關(guān)系。采用連鎖不平衡分析和生物信息學(xué)功能預(yù)測(cè)相結(jié)合的方法,選擇了IGF-1和IGF-1R上各五個(gè)標(biāo)簽單核苷酸多態(tài)性(target Single Nucleotide Polymorphisms,tag SNPs),并應(yīng)用Taq Man技術(shù)進(jìn)行基因分型。計(jì)量資料和計(jì)數(shù)資料分別采用兩樣本t檢驗(yàn)和卡方檢驗(yàn)比較病例組和對(duì)照組間臨床特征和基因型分布的差異。采用Logistic回歸模型評(píng)估病例對(duì)照中IGF-1及IGF-1R基因多態(tài)性和高血壓的關(guān)聯(lián),并用Cox比例風(fēng)險(xiǎn)回歸模型分析基因變異對(duì)高血壓發(fā)生的風(fēng)險(xiǎn)比。采用一般線(xiàn)性模型GLM分析血壓數(shù)量性狀之間的關(guān)系。HAPSTATA 3.0進(jìn)行單倍型分析,評(píng)估單體域的多個(gè)位點(diǎn)對(duì)高血壓的影響。結(jié)果:病例對(duì)照研究中,IGF-1和IGF-1R基因遺傳變異與高血壓關(guān)聯(lián)分析顯示,校正年齡、性別、TC、TG、HDL-C、LDL-C、GLU、BMI、吸煙和飲酒等混雜因素后,IGF-1R基因的rs1815009和rs2654981與原發(fā)性高血壓存在顯著關(guān)聯(lián),OR(95%CI)分別為0.905(0.831-0.986)和1.193(1.014-1.405)。進(jìn)一步分層分析發(fā)現(xiàn),IGF-1基因rs35767的變異在正常體重人群中是高血壓的保護(hù)因素,而在肥胖人群中是高血壓的危險(xiǎn)因素,OR(95%CI)分別為0.833(0.724-0.958)和1.345(1.021-1.773)。IGF-1R基因的rs2229765在55歲人群、不飲酒人群和超重人群中以及rs2002880在飲酒和超重人群中與原發(fā)性高血壓有統(tǒng)計(jì)學(xué)關(guān)聯(lián)(P0.05)。血壓數(shù)量性狀分析顯示在服用抗高血壓藥物組中rs6218、rs5742612和rs13379905不同基因型攜帶者之間的血壓水平有差異。單體型分析顯示,rs1815009和rs2654981位于同一Block。和常見(jiàn)單體型G-A相比,單體型A-A和高血壓存在顯著關(guān)聯(lián),校正OR(95%CI)為1.19(1.02-1.39),P=0.03。前瞻性隨訪(fǎng)發(fā)現(xiàn),校正年齡、性別、TC、TG、LDL-C、HDL-C、糖尿病、BMI、吸煙和飲酒混雜因素后,IGF-1R基因rs13379905的變異顯著增加高血壓的發(fā)病風(fēng)險(xiǎn),其不同基因型CC、CT、TT攜帶者的發(fā)病密度分別為6654.95、7755.36和8566.04(/10萬(wàn)人年),并且該關(guān)聯(lián)在非飲酒組和有高血壓家族人群中更顯著,HR(95%CI)分別為1.357(1.080-1.707)和2.100(1.381-3.194),P分別為0.009、0.001。IGF-1基因rs6219位點(diǎn)CT突變?cè)?5歲年齡組、肥胖和有高血壓家族史人群中顯著降低高血壓的發(fā)病風(fēng)險(xiǎn),在肥胖人群中rs2002880的AA基因型攜帶者相比GG基因型攜帶者降低高血壓的發(fā)病風(fēng)險(xiǎn)(P0.05)。兒童人群分析結(jié)果顯示,校正年齡、性別、BMI、TC、TG、HDL-C和LDL-C后,在男性?xún)和衦s13379905位點(diǎn)CT變異與高血壓前期以及高血壓前期合并高血壓呈正關(guān)聯(lián),OR(95%CI)分別為1.795(1.191-2.703),P=0.005;1.583(1.148-2.184),P=0.005。而在女性?xún)和性撐稽c(diǎn)變異與高血壓前期呈負(fù)關(guān)聯(lián),相加和顯性模型的OR(95%CI)分別為0.525(0.295-0.932),P=0.028;0.529(0.293-0.956),P=0.035。在男性?xún)和?rs13379905不同基因型(CC、CT、TT)的SBP的Z評(píng)分分別為1.04±0.97、1.09±1.03、1.89±0.66,呈線(xiàn)性增加趨勢(shì),P=0.042。血清IGF-1和IGF-1R水平在高血壓組和對(duì)照組之間的差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05),rs2002880位點(diǎn)GA基因型攜帶者血清IGF-1R水平高于GG攜帶者,P=0.011。結(jié)論:研究結(jié)果顯示IGF-1R基因多個(gè)位點(diǎn)變異與成人高血壓的發(fā)病存在關(guān)聯(lián),且rs13379905與男性?xún)和哐獕猴@著關(guān)聯(lián)。年齡、BMI和家族史對(duì)IGF-1基因變異與高血壓的關(guān)聯(lián)效應(yīng)具有修飾作用。這些結(jié)果均表明,IGF-1信號(hào)通路的遺傳變異可能影響高血壓的遺傳易感性。
[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.
【學(xué)位授予單位】：皖南醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R544.11
本文編號(hào)：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.
【學(xué)位授予單位】：皖南醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R544.11
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