基质金属蛋白酶-9基因及肝脂肪酶基因单核苷酸多态性与脑梗死的相关性研究
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摘要
目的:研究基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)基因及肝脂肪酶(hepatic lipase,HL)基因单核苷酸多态性(single nucletide polymorphisms,SNPs)与脑梗死(cerebral infarction,CI)的相关关系,进一步探讨脑梗死的发生机制。
方法:采用聚合酶链反应( polymerase chain reaction, PCR)及限制性片段长度多态性分析法(restriction fragment length polymorphism,RFLP)对100例CI患者、72例人群对照进行MMP-9基因R279Q、C-1562T及HL基因C-514T、A-763G位点多态性检测,所得数据用SPSS13.0统计软件包进行等位基因和基因频率分布的比较及基因联合作用与脑梗死的关联分析。
结果:
1.对CI组与人群对照组各基因分布行Hardy-Weinber遗传平衡检验(P>0.05)符合遗传平衡,具有群体代表性。
2.CI组与人群对照组比较,MMP-9基因R279Q多态性基因型(P=0.047)及等位基因频率(P=0.016)分布有显著性差异,R等位基因频率明显高于人群对照组(74%,61.8%),可能与脑梗死的发病有关。MMP-9基因C-1562T及HL基因C-514T、A-763G基因型(P>0.05)及等位基因频率(P>0.05)分布无显著性差异。
3.HL C-514T T等位基因与MMP-9 R279Q联合型分布在CI组与人群对照组中有显著性差异(χ2 =4.718,p=0.03),HL A-763G G等位基因与MMP-9 R279Q联合型分布差异有显著性(χ2 =3.870,p=0.049),HL C-514T C等位基因、A-763G A等位基因分别与MMP-9 R279Q的联合型分布无显著性差异,MMP-9 R279Q R等位基因, Q等位基因分别与HL C-514T,A-763G的联合型差异无显著性。
4.CI组与人群对照组的几项生化指标及性别、年龄、吸烟史、饮酒史等危险因素比较得出:高密度脂蛋白(P<0.001),高血压(P=0.0482),差异有显著性,其他指标差异均无显著性。
5.将MMP-9基因及HL基因各个多态性位点,年龄,血浆总胆固醇(TC),甘油三酯(TG),高密度脂蛋白(HDL)及饮酒史等可能的脑梗死危险因素纳入,进行Logistic回归分析,其中高血压(OR=14.277,95%CI=6.574-31.011,P <0.001)为脑梗死的危险因素,可增加脑梗死发生;高密度脂蛋白是保护性因素(OR=0.465<1),可减少CI的发生。MMP-9基因R279Q (OR=5.267,95%CI=2.059-13.471)可能是脑梗死的独立危险因素。其余未纳入回归方程.
结论:在河北省汉族人群中:
1. MMP-9 R279Q可能与脑梗死有关,可能是独立危险因素。
2. MMP-9 C-1562T可能与脑梗死无关。
3. HL C-514T T等位基因与MMP-9 R279Q联合型可能与脑梗死有关,
4.HL A-763G G等位基因与MMP-9 R279Q联合型可能与脑梗死有关。
5. HL C-514T C等位基因、A-763G A等位基因与MMP-9 R279Q的联合型与脑梗死无关。
6.MMP-9 R279Q R等位基因, Q等位基因分别与HL C-514T,A-763G的联合型与脑梗死无关。
Object: To study whether the single nucletide polymorphisms(SNPs) of matrix metalloproteinase-9 (MMP-9)gene and hepatic lipase (HL) gene are associated with cerebral infarction(CI) in Chinese,and furtherly discuss the mechanisms of the occurance of CI.
Method: Four mutations respectively at 279 fromR to Q,-1562 from C to T of MMP-9 gene and -514 from C to T,-763fromA to G of HL gene were determined in 100 patients with CI,72 contrals from the population in the epidemic survey by a combination of polymerase chain reaction(PCR) and restriction fragament length polymorphism(RFLP). Association study was performed to analyze the allele and gene frequency distribution and genetic comparison of combined effects of correlation analysis and CI on the basis ofthe data from statistical software package SPSS13.0
Result:
1.The gene distribution of Hardy-Weinber genetic equilibrium test (P> 0.05) consistent with the genetic balance, a group representative.
2.MMP-9 gene R279Q polymorphism genotype (P = 0.047) and allele frequency (P = 0.016) distribution has significant difference between CI and healthy controls. R allele frequency was significantly higher than healthy controls (74%, 61.8%), may be related to CI There were no statistical significance of distribution of MMP-9 gene C-1562T and the HL gene C-514T, A-763G genotype (P> 0.05) and allele frequencies (P> 0.05) .
3.There were statistical significance of distribution of HL C-514T T allele and MMP-9 R279Q combinated genes between between CI and healthy controls (χ2 = 4.718, p = 0.03),,and the distribution of HL A-763G G allele and MMP-9 R279Q combinated genes were also a significant difference (χ2 = 3.870, p = 0.049). there were no statistical significance of distribution of HL C-514T C allele ,HL A-763G A allele and MMP-9 R279Q combinated genes between CI and healthy controls ,and also no statistical significance of distribution of MMP-9 R279Q R allele, Q-type allele and the HL gene combinated genes
4.There were significantly difference of HDL(P=0.0482)and hypertension (P<0.001) between cerebral infraction and healthy controls.
5. When taking MMP-9 and the HL gene polymorphism locus genotype, age, plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and drinking history and other potential risk factors into consideration, the Logistic regression analysis showed hypertension (OR=14.277,95%CI=6.574-31.011,P <0.001)was risk factor.,and HDLwas protective factor(OR=0.082<1). MMP-9 geneMMP-9 R279Q (OR = 5.267,95% CI = 2.059-13.471) may be risk factors for CI
Conclusion:
These suggested that in HeBei province Han people MMP-9 R279Q may be related to cerebral infarction , which may be an independent risk factor .MMP-9 C-1562T and HL gene was not the risk factors for CI..There were some relations between combinated genes(C-514T T and R279Q;A-763G G and R279Q) and CI,while no relations between combinated genes(C-514T C and R279Q ;A-763G A and R279Q ;R279Q R and C-514T; R279Q Q and C-514T; R279Q R and A-763G;R279Q Q and A-763G A)and CI.
方法:采用聚合酶链反应( polymerase chain reaction, PCR)及限制性片段长度多态性分析法(restriction fragment length polymorphism,RFLP)对100例CI患者、72例人群对照进行MMP-9基因R279Q、C-1562T及HL基因C-514T、A-763G位点多态性检测,所得数据用SPSS13.0统计软件包进行等位基因和基因频率分布的比较及基因联合作用与脑梗死的关联分析。
结果:
1.对CI组与人群对照组各基因分布行Hardy-Weinber遗传平衡检验(P>0.05)符合遗传平衡,具有群体代表性。
2.CI组与人群对照组比较,MMP-9基因R279Q多态性基因型(P=0.047)及等位基因频率(P=0.016)分布有显著性差异,R等位基因频率明显高于人群对照组(74%,61.8%),可能与脑梗死的发病有关。MMP-9基因C-1562T及HL基因C-514T、A-763G基因型(P>0.05)及等位基因频率(P>0.05)分布无显著性差异。
3.HL C-514T T等位基因与MMP-9 R279Q联合型分布在CI组与人群对照组中有显著性差异(χ2 =4.718,p=0.03),HL A-763G G等位基因与MMP-9 R279Q联合型分布差异有显著性(χ2 =3.870,p=0.049),HL C-514T C等位基因、A-763G A等位基因分别与MMP-9 R279Q的联合型分布无显著性差异,MMP-9 R279Q R等位基因, Q等位基因分别与HL C-514T,A-763G的联合型差异无显著性。
4.CI组与人群对照组的几项生化指标及性别、年龄、吸烟史、饮酒史等危险因素比较得出:高密度脂蛋白(P<0.001),高血压(P=0.0482),差异有显著性,其他指标差异均无显著性。
5.将MMP-9基因及HL基因各个多态性位点,年龄,血浆总胆固醇(TC),甘油三酯(TG),高密度脂蛋白(HDL)及饮酒史等可能的脑梗死危险因素纳入,进行Logistic回归分析,其中高血压(OR=14.277,95%CI=6.574-31.011,P <0.001)为脑梗死的危险因素,可增加脑梗死发生;高密度脂蛋白是保护性因素(OR=0.465<1),可减少CI的发生。MMP-9基因R279Q (OR=5.267,95%CI=2.059-13.471)可能是脑梗死的独立危险因素。其余未纳入回归方程.
结论:在河北省汉族人群中:
1. MMP-9 R279Q可能与脑梗死有关,可能是独立危险因素。
2. MMP-9 C-1562T可能与脑梗死无关。
3. HL C-514T T等位基因与MMP-9 R279Q联合型可能与脑梗死有关,
4.HL A-763G G等位基因与MMP-9 R279Q联合型可能与脑梗死有关。
5. HL C-514T C等位基因、A-763G A等位基因与MMP-9 R279Q的联合型与脑梗死无关。
6.MMP-9 R279Q R等位基因, Q等位基因分别与HL C-514T,A-763G的联合型与脑梗死无关。
Object: To study whether the single nucletide polymorphisms(SNPs) of matrix metalloproteinase-9 (MMP-9)gene and hepatic lipase (HL) gene are associated with cerebral infarction(CI) in Chinese,and furtherly discuss the mechanisms of the occurance of CI.
Method: Four mutations respectively at 279 fromR to Q,-1562 from C to T of MMP-9 gene and -514 from C to T,-763fromA to G of HL gene were determined in 100 patients with CI,72 contrals from the population in the epidemic survey by a combination of polymerase chain reaction(PCR) and restriction fragament length polymorphism(RFLP). Association study was performed to analyze the allele and gene frequency distribution and genetic comparison of combined effects of correlation analysis and CI on the basis ofthe data from statistical software package SPSS13.0
Result:
1.The gene distribution of Hardy-Weinber genetic equilibrium test (P> 0.05) consistent with the genetic balance, a group representative.
2.MMP-9 gene R279Q polymorphism genotype (P = 0.047) and allele frequency (P = 0.016) distribution has significant difference between CI and healthy controls. R allele frequency was significantly higher than healthy controls (74%, 61.8%), may be related to CI There were no statistical significance of distribution of MMP-9 gene C-1562T and the HL gene C-514T, A-763G genotype (P> 0.05) and allele frequencies (P> 0.05) .
3.There were statistical significance of distribution of HL C-514T T allele and MMP-9 R279Q combinated genes between between CI and healthy controls (χ2 = 4.718, p = 0.03),,and the distribution of HL A-763G G allele and MMP-9 R279Q combinated genes were also a significant difference (χ2 = 3.870, p = 0.049). there were no statistical significance of distribution of HL C-514T C allele ,HL A-763G A allele and MMP-9 R279Q combinated genes between CI and healthy controls ,and also no statistical significance of distribution of MMP-9 R279Q R allele, Q-type allele and the HL gene combinated genes
4.There were significantly difference of HDL(P=0.0482)and hypertension (P<0.001) between cerebral infraction and healthy controls.
5. When taking MMP-9 and the HL gene polymorphism locus genotype, age, plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and drinking history and other potential risk factors into consideration, the Logistic regression analysis showed hypertension (OR=14.277,95%CI=6.574-31.011,P <0.001)was risk factor.,and HDLwas protective factor(OR=0.082<1). MMP-9 geneMMP-9 R279Q (OR = 5.267,95% CI = 2.059-13.471) may be risk factors for CI
Conclusion:
These suggested that in HeBei province Han people MMP-9 R279Q may be related to cerebral infarction , which may be an independent risk factor .MMP-9 C-1562T and HL gene was not the risk factors for CI..There were some relations between combinated genes(C-514T T and R279Q;A-763G G and R279Q) and CI,while no relations between combinated genes(C-514T C and R279Q ;A-763G A and R279Q ;R279Q R and C-514T; R279Q Q and C-514T; R279Q R and A-763G;R279Q Q and A-763G A)and CI.
引文
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30 Zambon A , Brown BG, Deeb SS , et al .Hepatic lipase as a focal point for the development and treatment of coronary artery disease.J Investig Med , 2001 ,49(1):112-118
31 Allayee HKM ,Dominguez BE,Aonizerat RM ,et al .Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype infamilial combined hyperlipidemia.JLipidRes,2000,41(2):245-252
32 Zambon A , Deeb SS , Bensadoun A , et al . In vivo evidence of a role for hepatic lipase in human apoB containing lipoprotein metabolism , independent of its lipolytic activity. J Lipid Res , 2000,41(12):2094-2099
33 Lee SJ , Kadambi S , Yu KC , et al . Removal of chylomicron remnant s in transgenic mice overexpressing normal and membraneanchored hepatic lipase.J Lipid Res ,2005,46 (1):27-35
34 Gonzalez2Navarro H , Nong Z , Amar MJ ,et al.The ligandbinding function of hepatic lipase modulates the development of atherosclerosis in transgenic mice. J Biol Chem,2004,279 (44):45312-45321
35 Deeb SS , Zambon A , Carr MC , et al . Hepatic lipase and dyslipidemia : in teractions among alnetic variants , obesity , gender and diet .J Lipid Res ,2003,44(7):1279-1317
36 Berg GA , Siecles N , Gouzalez AI ,et al.Higher values of hepatic lipase activity in postmenpause : Relationship with at herogenic internnediated density and low density lipoproteins. Menopause ,2001 , 8(1):51-57
37张晓刚,陈运贞.低密度脂蛋白和氧化型低密度脂蛋白对Hep G2细胞肝脂酶活性及肝脂酶mRNA表达的影响.中国动脉硬化杂志,2003,11 (2):147-150
38 Ji J ,Herbison CE , Mamotte CD , et al . Hepatic lipase gene 514C/T Polymorphism and premature coronary disease.J Cardiovasc Risk ,2002, 9(2):105-113
39 Isaacs A , Sayed-Tabatabaei FA , Njajou OT , etal.The -514C/T hepatic Lipase promoter region polymorphism and plasma lipids : a meta-analysis. J Clin Endocrinol Metab , 2004 ,89 ( 8 ):3858-3862
40 Andrade FM , Silveira FR , Arsand M , et al .Association between 2250 G/A polymorphism of the hepatic lipase gene promoter and coronary artery disease and HDL-C levels in a Sout hern Brazilian population. Clin Genet ,2004,5(5):390-395
41 Couture P, Otvos J D, Cupp les L A, et al. Association of the C-514T polymorphism in the hepatic lipase gene with variations inlipoprotein subclass profiles: The Framingham Offspring Study.Arterioscler Thromb Vasc Biol,2000,20(3):815-822
42 Hubacek JA,Nishmura Y,Terada Y,etal.Effects of hepatic lipase gene promoter nucleotide variations on serum HDL,cholesterol concentration In the general Japanese population .JHum Genet,2001,46(4):172-177
43王云玲,倪培华,应雅韵,等.肝脂酶基因启动子710 T/C、763A/G多态性与脑梗死的关系.卒中与神经疾病杂志, 2007; 14(2) : 96-101
44刘运海,黄清,杨期东,等.血清对氧磷酶L55M基因多态性与动脉粥样硬化性脑梗死的关系.临床神经病学杂志,2005,18:244
45宋云,田桂玲,王彤宁,等.血清对氧磷酯酶21活性及其基因多态性与动脉粥样硬化性血栓性脑梗死关系的研究.临床神经病学杂志,2007,20:170
46 Shih DM,Gu L,Xia YR,etal.Mice lacking serum paraoxonase are suscetiptible to organophosphate toxiciy and athersclerosis . Nature:1998,394:284-287
47 Aviram M, Hardak E, Vaya J, et al. Human serum paraoxonase (PON1)Qand R selectively decrease lipid peroxides in human coronar and carotid atherosclerotic lesions: PON1 esterase and peroxidase likactivities. Circulation, 2000, 101: 2510
48 Ng CJ, Wadleigh DJ, GangopadhyayA, et al. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of lowdensity lipoprotein. J Biol Chem,2001,276:44444
49 RosenblatM, Draganov D, Watson CE, etal.Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol, 2003,23:468
50 RosenblatM, Hayek T, Hussein K, et al.Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy.Arterioscler Thromb Vasc Biol, 2004,24:175
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29马莎,蒋凌月.IL-6基因调控区-174G/C多态性与急性脑梗死的关系.中风与神经疾病杂志,2003 ,20(2):152-154
30 Zambon A , Brown BG, Deeb SS , et al .Hepatic lipase as a focal point for the development and treatment of coronary artery disease.J Investig Med , 2001 ,49(1):112-118
31 Allayee HKM ,Dominguez BE,Aonizerat RM ,et al .Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype infamilial combined hyperlipidemia.JLipidRes,2000,41(2):245-252
32 Zambon A , Deeb SS , Bensadoun A , et al . In vivo evidence of a role for hepatic lipase in human apoB containing lipoprotein metabolism , independent of its lipolytic activity. J Lipid Res , 2000,41(12):2094-2099
33 Lee SJ , Kadambi S , Yu KC , et al . Removal of chylomicron remnant s in transgenic mice overexpressing normal and membraneanchored hepatic lipase.J Lipid Res ,2005,46 (1):27-35
34 Gonzalez2Navarro H , Nong Z , Amar MJ ,et al.The ligandbinding function of hepatic lipase modulates the development of atherosclerosis in transgenic mice. J Biol Chem,2004,279 (44):45312-45321
35 Deeb SS , Zambon A , Carr MC , et al . Hepatic lipase and dyslipidemia : in teractions among alnetic variants , obesity , gender and diet .J Lipid Res ,2003,44(7):1279-1317
36 Berg GA , Siecles N , Gouzalez AI ,et al.Higher values of hepatic lipase activity in postmenpause : Relationship with at herogenic internnediated density and low density lipoproteins. Menopause ,2001 , 8(1):51-57
37张晓刚,陈运贞.低密度脂蛋白和氧化型低密度脂蛋白对Hep G2细胞肝脂酶活性及肝脂酶mRNA表达的影响.中国动脉硬化杂志,2003,11 (2):147-150
38 Ji J ,Herbison CE , Mamotte CD , et al . Hepatic lipase gene 514C/T Polymorphism and premature coronary disease.J Cardiovasc Risk ,2002, 9(2):105-113
39 Isaacs A , Sayed-Tabatabaei FA , Njajou OT , etal.The -514C/T hepatic Lipase promoter region polymorphism and plasma lipids : a meta-analysis. J Clin Endocrinol Metab , 2004 ,89 ( 8 ):3858-3862
40 Andrade FM , Silveira FR , Arsand M , et al .Association between 2250 G/A polymorphism of the hepatic lipase gene promoter and coronary artery disease and HDL-C levels in a Sout hern Brazilian population. Clin Genet ,2004,5(5):390-395
41 Couture P, Otvos J D, Cupp les L A, et al. Association of the C-514T polymorphism in the hepatic lipase gene with variations inlipoprotein subclass profiles: The Framingham Offspring Study.Arterioscler Thromb Vasc Biol,2000,20(3):815-822
42 Hubacek JA,Nishmura Y,Terada Y,etal.Effects of hepatic lipase gene promoter nucleotide variations on serum HDL,cholesterol concentration In the general Japanese population .JHum Genet,2001,46(4):172-177
43王云玲,倪培华,应雅韵,等.肝脂酶基因启动子710 T/C、763A/G多态性与脑梗死的关系.卒中与神经疾病杂志, 2007; 14(2) : 96-101
44刘运海,黄清,杨期东,等.血清对氧磷酶L55M基因多态性与动脉粥样硬化性脑梗死的关系.临床神经病学杂志,2005,18:244
45宋云,田桂玲,王彤宁,等.血清对氧磷酯酶21活性及其基因多态性与动脉粥样硬化性血栓性脑梗死关系的研究.临床神经病学杂志,2007,20:170
46 Shih DM,Gu L,Xia YR,etal.Mice lacking serum paraoxonase are suscetiptible to organophosphate toxiciy and athersclerosis . Nature:1998,394:284-287
47 Aviram M, Hardak E, Vaya J, et al. Human serum paraoxonase (PON1)Qand R selectively decrease lipid peroxides in human coronar and carotid atherosclerotic lesions: PON1 esterase and peroxidase likactivities. Circulation, 2000, 101: 2510
48 Ng CJ, Wadleigh DJ, GangopadhyayA, et al. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of lowdensity lipoprotein. J Biol Chem,2001,276:44444
49 RosenblatM, Draganov D, Watson CE, etal.Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol, 2003,23:468
50 RosenblatM, Hayek T, Hussein K, et al.Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy.Arterioscler Thromb Vasc Biol, 2004,24:175
51 Hegele RA, Connelly PW, Scherer SW, et al. Paraoxonase-2 gene( PON2) G148 variant associated with elevated fasting plasma glucose in noninsul-independent diabetesmellitus.J Clin Endocrin Metabol, 1997,82:3373
52冯雁,李琼芳,钱荣立,等.二乙基对硝基苯磷酯酶-2基因G148A多态性与2型糖尿病及血脂的关系[J].中国糖尿病杂志, 2002,10:195
53郝云玲,林丽香,陈刚.对氧磷酯酶基因多态性与糖尿病肾病的关系.中华肾脏病杂志,2002,18:422
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