高血压并心力衰竭与SLC6A2、ACE基因多态性的关联研究
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摘要
目的:探讨去甲肾上腺素转运蛋白SLC6A2基因(Norepinephrine transporter,NET)启动子3 (rs=168924)、血管紧张素转换酶(ACE)基因多态性(insertion,I/ deletion, D;rs1799998)与高血压病合并心力衰竭的相关性。
方法:收集176例心功能Ⅲ-Ⅳ级的高血压病并心力衰竭汉族患者(EH-HF组),及与之按性别、年龄±4、居住地相匹配的心功能正常的高血压病患者(EH组)及血压心功能正常对照组(Control组)各176例。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测SLC6A2启动子3的A/G多态性及ACE(I/D)多态性基因型。采用χ2检验比较三组不同基因型及基因型组合分布频率, Hardy-Weinberg平衡用拟合χ2检验,筛查和调整危险因素用多因素二项或多项Logistic回归分析(Binary Logistic Regression, Multinomial Logistic Regression)。结果:1、Hardy-Weinberg遗传平衡检验示:SLC6A2基因和ACE基因不同基因型分布符合Hardy-Weinberg遗传平衡(P均>0.05),样本具有群体代表性。
2、EH-HF、EH和对照三组SLC6A2基因的AA、AG和GG基因型构成比总的分布有显著性差异(χ2=17.063,P<0.001);经进一步卡方分割检验显示EH-HF组AG/GG基因型频率(41.48%)高于EH组(26.70%)和Control组(22.16%),差异显著(χ2=7.937,P=0.005),三组ACE基因的II、ID和DD基因型构成比总的分布有显著性差异(χ2=19.858,P=0.001);经进一步卡方分割检验显示EH-HF组DD基因型频率(26.14%)高于EH组(12.50%)和Control组(10.80%),差异显著(χ2=17.897,P<0.001),三组不同基因组合DD+AG/GG、DD+AA、II/ID+AG/GG、II/ID+AA型构成比总的分布有显著性差异(χ2=34.604,P<0.001);经进一步卡方分割检验显示EH-HF组DD+AG/GG基因型频率(11.36%)高于EH组(3.41%)和Control组(1.70%),差异显著(χ2=17.532,P<0.001)。
3.经多因素Logistic回归,以EH组为参照系筛查出吸烟、血糖升高、肾功能减退、高血压等级、ACE-DD型、SLC6A2-AG/GG型及DD+AG/GG型是主要危险因素,其中经调整了其他危险因素的影响后,SLC6A2-AG/GG、ACE-DD型相对危险度(OR)值分别为1.905 (95%CI:1.138-3.188,P=0.014)和1.908 (95%CI:1.009-3.609,P=0.047)。设定II/ID+AA为参考分类(OR=1),调整其他危险因素后,DD+AG/GG基因型相对危险度最大,OR值为3.446 (95%CI:1.195-9.940),提示二种基因协同作用与高血压病并心力衰竭患者有显著性相关。
结论:携带有ACE-DD型、SLC6A2-AG/GG型及DD+AG/GG型可能是高血压病合并心力衰竭独立危险因素,同时携带有这二种基因型对患高血压病并心力衰竭风险最大。
Objective: To investigat the association between polymorphisms of the norepinephrine transporter gene(solute carrier family 6, member 2; SLC6A2 promoter 3 ) angiotensin converting enzyme(ACE) gene insertion/deletion and essential hypertension complicated by heart failure.
Methods: We collected EH-HF group of 176 subjects with NYHAⅢ-Ⅳfunctional class, and matched EH group with normal functional class and control subjects controlling for individual age±4, gender and geography. SLC6A2 gene-promoter3-G/C, ACE gene-I/D polymorphisms were determined with the use of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism methods,and polymorphic frequencies were compared in patients with EH-HF, EH group and control. Information about prior exposure to various potential risk factors was also obtained. Chi-square test was used to compare difference of genotypes distribution among three groups. The Hardy-Weinberg equilibrium was tested by Chi-square test of goodness of fit. Odds ratios for these comparisons of dangerous factors were calculated by Binary and Multinomial Logistic Regression.
Results: 1. Both ACE-I/D and SLC6A2-promoter3 polymorphism exhibited a nonsignificant difference by the Hardy-Weinberg equilibrium in control. 2. Chi-square test showed significant difference for SLC6A2-AA, AG and GG genotypes distribution in the three groups(χ2=17.063,P<0.001), and then Partitions ofχ2 method indicated that SLC6A2-AG/GG genotype frequencies in EH-HF group(41.48%) were significantly higher than those in EH group(26.70%)and Control group(22.16%) (χ2=7.937,P=0.005). The constituent ratio of ACE-II, ID, DD genotype was significantly different in the three groups(χ2=19.858,P=0.001), and then Partitions ofχ2 method showed that ACE–DD genotype frequencies in EH-HF group(26.14%) were significantly higher than those in EH group(12.50%)and Control group(22.16%)(χ2=17.897,P<0.001). The 2 gene conjoint Analysis indicated significant difference of combined genotype frequencies in the three groups (χ2=34.604 , P < 0.001), furthermore, and Partitions ofχ2 method showed that DD+AG/GG genotype frequencies in EH-HF group(11.36%) were significantly higher than those in EH group(3.41%)and Control group(1.70%)(χ2=17.532,P<0.001).
3. Multinomial logistic-regression Analysis indicated that Smoke, High blood sugar, Kidney hypofunction, Blood Pressure Levels, ACE-DD genotype, SLC6A2-AG/GG genotype and combined DD+AG/GG genotype were risk factors for EH-HF with the reference category of EH. The odds ratios(OR) of the SLC6A2-AG/GG genotype vs AA and ACE-DD genotype vs II/ID for EH-HF were 1.905 (95%CI: 1.138-3.188,P=0.014) and 1.908 (95%CI: 1.009-3.609,P=0.047) after adjusting other confounding factors, respectively. If II/ID+AA genotype was made reference frame(OR=1), maximal OR was significantly found after adjustment: OR for DD+AG/GG genotype vs the other was 3.446 (95%CI: 1.195-9.940). It is suggested that the cooperation of two genes was significantly associated with hypertension complicated with heart failure.
Conclusion: SLC6A2-GG/AG, ACE-DD and DD+AG/GG genotype may be the independent risk factors of hypertensive patients with heart failure。DD+AG/GG genotype are significantly associated with EH-HF and have the highest risk in EH-HF、and may be one of the genes that contribute to EH-HF in Chinese. It suggests that ACE and SLC6A2 gene have synergistic action in the pathogenesis of EH-HF.
方法:收集176例心功能Ⅲ-Ⅳ级的高血压病并心力衰竭汉族患者(EH-HF组),及与之按性别、年龄±4、居住地相匹配的心功能正常的高血压病患者(EH组)及血压心功能正常对照组(Control组)各176例。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测SLC6A2启动子3的A/G多态性及ACE(I/D)多态性基因型。采用χ2检验比较三组不同基因型及基因型组合分布频率, Hardy-Weinberg平衡用拟合χ2检验,筛查和调整危险因素用多因素二项或多项Logistic回归分析(Binary Logistic Regression, Multinomial Logistic Regression)。结果:1、Hardy-Weinberg遗传平衡检验示:SLC6A2基因和ACE基因不同基因型分布符合Hardy-Weinberg遗传平衡(P均>0.05),样本具有群体代表性。
2、EH-HF、EH和对照三组SLC6A2基因的AA、AG和GG基因型构成比总的分布有显著性差异(χ2=17.063,P<0.001);经进一步卡方分割检验显示EH-HF组AG/GG基因型频率(41.48%)高于EH组(26.70%)和Control组(22.16%),差异显著(χ2=7.937,P=0.005),三组ACE基因的II、ID和DD基因型构成比总的分布有显著性差异(χ2=19.858,P=0.001);经进一步卡方分割检验显示EH-HF组DD基因型频率(26.14%)高于EH组(12.50%)和Control组(10.80%),差异显著(χ2=17.897,P<0.001),三组不同基因组合DD+AG/GG、DD+AA、II/ID+AG/GG、II/ID+AA型构成比总的分布有显著性差异(χ2=34.604,P<0.001);经进一步卡方分割检验显示EH-HF组DD+AG/GG基因型频率(11.36%)高于EH组(3.41%)和Control组(1.70%),差异显著(χ2=17.532,P<0.001)。
3.经多因素Logistic回归,以EH组为参照系筛查出吸烟、血糖升高、肾功能减退、高血压等级、ACE-DD型、SLC6A2-AG/GG型及DD+AG/GG型是主要危险因素,其中经调整了其他危险因素的影响后,SLC6A2-AG/GG、ACE-DD型相对危险度(OR)值分别为1.905 (95%CI:1.138-3.188,P=0.014)和1.908 (95%CI:1.009-3.609,P=0.047)。设定II/ID+AA为参考分类(OR=1),调整其他危险因素后,DD+AG/GG基因型相对危险度最大,OR值为3.446 (95%CI:1.195-9.940),提示二种基因协同作用与高血压病并心力衰竭患者有显著性相关。
结论:携带有ACE-DD型、SLC6A2-AG/GG型及DD+AG/GG型可能是高血压病合并心力衰竭独立危险因素,同时携带有这二种基因型对患高血压病并心力衰竭风险最大。
Objective: To investigat the association between polymorphisms of the norepinephrine transporter gene(solute carrier family 6, member 2; SLC6A2 promoter 3 ) angiotensin converting enzyme(ACE) gene insertion/deletion and essential hypertension complicated by heart failure.
Methods: We collected EH-HF group of 176 subjects with NYHAⅢ-Ⅳfunctional class, and matched EH group with normal functional class and control subjects controlling for individual age±4, gender and geography. SLC6A2 gene-promoter3-G/C, ACE gene-I/D polymorphisms were determined with the use of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism methods,and polymorphic frequencies were compared in patients with EH-HF, EH group and control. Information about prior exposure to various potential risk factors was also obtained. Chi-square test was used to compare difference of genotypes distribution among three groups. The Hardy-Weinberg equilibrium was tested by Chi-square test of goodness of fit. Odds ratios for these comparisons of dangerous factors were calculated by Binary and Multinomial Logistic Regression.
Results: 1. Both ACE-I/D and SLC6A2-promoter3 polymorphism exhibited a nonsignificant difference by the Hardy-Weinberg equilibrium in control. 2. Chi-square test showed significant difference for SLC6A2-AA, AG and GG genotypes distribution in the three groups(χ2=17.063,P<0.001), and then Partitions ofχ2 method indicated that SLC6A2-AG/GG genotype frequencies in EH-HF group(41.48%) were significantly higher than those in EH group(26.70%)and Control group(22.16%) (χ2=7.937,P=0.005). The constituent ratio of ACE-II, ID, DD genotype was significantly different in the three groups(χ2=19.858,P=0.001), and then Partitions ofχ2 method showed that ACE–DD genotype frequencies in EH-HF group(26.14%) were significantly higher than those in EH group(12.50%)and Control group(22.16%)(χ2=17.897,P<0.001). The 2 gene conjoint Analysis indicated significant difference of combined genotype frequencies in the three groups (χ2=34.604 , P < 0.001), furthermore, and Partitions ofχ2 method showed that DD+AG/GG genotype frequencies in EH-HF group(11.36%) were significantly higher than those in EH group(3.41%)and Control group(1.70%)(χ2=17.532,P<0.001).
3. Multinomial logistic-regression Analysis indicated that Smoke, High blood sugar, Kidney hypofunction, Blood Pressure Levels, ACE-DD genotype, SLC6A2-AG/GG genotype and combined DD+AG/GG genotype were risk factors for EH-HF with the reference category of EH. The odds ratios(OR) of the SLC6A2-AG/GG genotype vs AA and ACE-DD genotype vs II/ID for EH-HF were 1.905 (95%CI: 1.138-3.188,P=0.014) and 1.908 (95%CI: 1.009-3.609,P=0.047) after adjusting other confounding factors, respectively. If II/ID+AA genotype was made reference frame(OR=1), maximal OR was significantly found after adjustment: OR for DD+AG/GG genotype vs the other was 3.446 (95%CI: 1.195-9.940). It is suggested that the cooperation of two genes was significantly associated with hypertension complicated with heart failure.
Conclusion: SLC6A2-GG/AG, ACE-DD and DD+AG/GG genotype may be the independent risk factors of hypertensive patients with heart failure。DD+AG/GG genotype are significantly associated with EH-HF and have the highest risk in EH-HF、and may be one of the genes that contribute to EH-HF in Chinese. It suggests that ACE and SLC6A2 gene have synergistic action in the pathogenesis of EH-HF.
引文
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17.Mason DA。Moore JD。Green SA.et a1.A gain-of-funotion polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor.J. Biol Chem 1999;274(18):12670-12674
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23 Strazzullo P,Iacone R, Siani A,et a1. Relationship of the Trp64Arg polymorphism of the β3-adrenoceptor gene to central adiposity and high blood pressure:interaction with age.Crosssectional and longitudinal findings of the Olivetti ProspectiveHeart Study[J].J Hypertens,2001..19(3):399-406.
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31.刘旭东,李锦毅,史晶,等. 去甲肾上腺素转运蛋白的研究进展. 武警医学, 2005,16(4):294-296
32.Pacholczyk T, Blakely RD, Amara SG. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature, 1991, 350(6316): 350-354.
33.Rumantir MS, Kaye DM, Jennings GR, Vaz M, Hastings JA, Esler MD: Phenotypic evidence of faulty neuronal norepinephrine reuptake in essential hypertension. Hypertension 2000; 36: 824-829.
34.Ono K, Iwanaga Y, Mannami T, Kokubo Y, et al. Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension. Hypertens Res, 2003, 26(9):685-689.
35. Schlaich MP,Lambert E,Kaye DM et a1.Sympathetic Augmentation in Hypertension Role of Nerve Firing,Norepinephrine Reuptake,and Angitensin Neuromodulation.Hypertension,2004,43(2):169-175
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37.Sharma P, Hingorani A, Jia H et a1.Positive asseiation of tyroeine hydroxylse microsatellite marker to essential hyperternsion.Hypertension 1998,32 (4):676-682.Hypertension,1998,32:676-682
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