β纤维蛋白原基因-455G/A多态性与急性心肌梗死的关系研究
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摘要
目的：通过检测急性心肌梗死患者及对照人员的β纤维蛋白原基因-455G／A多态性，探讨该多态性与急性心肌梗死发病的关系，寻找急性心肌梗死发病的遗传性危险因素。对象：急性心肌梗死患者40例，均符合世界卫生组织关于急性心肌梗死的诊断标准。对照组40人(排除有冠心病、缺血性脑卒中及外周血管血栓疾病者)。方法：β纤维蛋白原-455基因多态性分析：(1)碘化钾法提取人基因组DNA；(2)多聚酶链反应(PCR)扩增目的基因片段；(3)扩增目的基因片段加Hae Ⅲ限制性内切酶水浴消化；(4)酶切产物经3％琼脂糖凝胶电泳分离后，紫外灯下检测酶切结果。SPSS11.5软件分析数据。结果：(1)急性心肌梗死组中β纤维蛋白原-455A等位基因频率显著高于对照组。(2)急性心肌梗死组中β纤维蛋白原-455GA和AA基因型携带者频率显著高于对照组。(3)在β纤维蛋白原-455三种基因型之间，高血压病、糖尿病发病率无显著性差异。(4)在β纤维蛋白原-455三种基因型之间，空腹血清甘油三脂、血糖及总胆固醇浓度无显著性差异。(5)急性心肌梗死组中合并糖尿病患者的发病频率显著高于对照组。(6)急性心肌梗死组中空腹甘油三脂及平均血糖浓度显著高于对照组。(7)多元logistic回归分析发现，性别、血糖及β纤维蛋白原-455AA+GA基因型对急性心肌梗死的发病有明显影响作用。结论：(1)β纤维蛋白原-455A等位基因可能是急性心肌梗死发病的遗传性危险因素。(2)β纤维蛋白原-455G／A多态性可能与高血压病和糖尿病的发病无关。(3)β纤维蛋白原-455G／A多态性可能与甘油三脂及总胆固醇代谢无关。(5)急性心肌梗死发病与性别、血清甘油三脂和血糖水平有关。
Objectives: To analyze the frequency of -fibrinogen gene -455 genotypes in acute myocardial infarction (AMI) group and control group. To investigate wether the -455G/A polymorphisms were associatied with the risk of AMI. To demonstrate wether possession of the -455A allele is a genetic risk of AMI. Subject and Methods: Forty patients suffered from acute myocardial infarction within one week, as defined by World Health Organization criteria. And forty control subjected were recruited. The participators in cnotrol group had no histories of coronary heart disease, ischemic stroke and peripheral arterial disease. The -455 polymorphism in the -fibrinogen gene were detected by polymerase chair reaction amplication of fragments of DNA by using specific oligonucleotide primers in a thermal cycler. Polymerase chain reaction products were subjected to 3 hours digestion by 4U HaeIII restriction enzymes at 37 C. Restricted DNA products were then separated by useng 3% agarose gel electrophoresis and visuslized by UV lig
ht. Interactions between these changes and other factors were analyzed with SPSS statistical software 11.5. Result: (1) There were signiferences diferrences in fibrinogen -455A allele distributions between AMI and in control groups, the frequence of -455A allele were higher in AMI group than control group. (2) There were signiferences diferrences in fibrinogen -455 genotype distributions between AMI and control groups, the frequence of -455AA and GG genotypes in AMI group were higher than that in control group. (3) There were no signiferences diferrences in hypertension and diabates groups in three fibrinogen -455 genotypes. (4) There were no signiferences diferrences in free plasma blood sugar, total cholesterol and triglyceride levels in three fibrinogen -455 genotypes. (5) Levels of sugar and blood triglyceride were higher in patients than that in control subjects. (5) fibrinogen
-455GA and AA genotypes were contribute with acute myocardial infarction. (6)Sex and blood sugar were contribute with acute myocardial infarction. Conclusion: (1) Fibrinogen β -455G/A polymorphisms is a genetic risk factor of acute myocardial infarction. (2) Fibrinogen β -455G/A polymorphisms have no associations with hypertension and diabetes. (3) Fibrinogen 3 -455G/A polymorphisms have no associations with the metabolism of sugar, cholesterol and triglyceride. (4) Sex, blood sugar and triglyceride have associations with AMI.
Objectives: To analyze the frequency of -fibrinogen gene -455 genotypes in acute myocardial infarction (AMI) group and control group. To investigate wether the -455G/A polymorphisms were associatied with the risk of AMI. To demonstrate wether possession of the -455A allele is a genetic risk of AMI. Subject and Methods: Forty patients suffered from acute myocardial infarction within one week, as defined by World Health Organization criteria. And forty control subjected were recruited. The participators in cnotrol group had no histories of coronary heart disease, ischemic stroke and peripheral arterial disease. The -455 polymorphism in the -fibrinogen gene were detected by polymerase chair reaction amplication of fragments of DNA by using specific oligonucleotide primers in a thermal cycler. Polymerase chain reaction products were subjected to 3 hours digestion by 4U HaeIII restriction enzymes at 37 C. Restricted DNA products were then separated by useng 3% agarose gel electrophoresis and visuslized by UV lig
ht. Interactions between these changes and other factors were analyzed with SPSS statistical software 11.5. Result: (1) There were signiferences diferrences in fibrinogen -455A allele distributions between AMI and in control groups, the frequence of -455A allele were higher in AMI group than control group. (2) There were signiferences diferrences in fibrinogen -455 genotype distributions between AMI and control groups, the frequence of -455AA and GG genotypes in AMI group were higher than that in control group. (3) There were no signiferences diferrences in hypertension and diabates groups in three fibrinogen -455 genotypes. (4) There were no signiferences diferrences in free plasma blood sugar, total cholesterol and triglyceride levels in three fibrinogen -455 genotypes. (5) Levels of sugar and blood triglyceride were higher in patients than that in control subjects. (5) fibrinogen
-455GA and AA genotypes were contribute with acute myocardial infarction. (6)Sex and blood sugar were contribute with acute myocardial infarction. Conclusion: (1) Fibrinogen β -455G/A polymorphisms is a genetic risk factor of acute myocardial infarction. (2) Fibrinogen β -455G/A polymorphisms have no associations with hypertension and diabetes. (3) Fibrinogen 3 -455G/A polymorphisms have no associations with the metabolism of sugar, cholesterol and triglyceride. (4) Sex, blood sugar and triglyceride have associations with AMI.
引文
1 王薇．冠心病流行病学和人群防治．见：吴兆苏主编．心血管疾病流行病学及防治(第一版)．北京人民卫生出版社,2002：2(1)22～26
2 吴兆苏，姚崇华，赵冬，等．我国多省市心血管病趋势及决定因素的人群监测(中国MONICA方案)．中华心血管病杂志，1997；25(1)6～11
3 国家“八五”攻关心脑血管病高发社区人群综合性预防研究课题协作组：心脑血管病社区人群综合性预防研究．中华预防医学杂志，1998，2(增刊)：3
4 吴锡桂，顾东风，李世绰，等．社区人群干预对心脑血管疾病危险因素水平的影响．中华预防医学杂志，1998，2(增刊)：16
5 洪震，黄茂盛，周玢，等．上海市静安区社区人群心脑血管病综合防治及其效果．中华预防医学杂志，1998，2(增刊)：39
6 Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med, 1984;310:1137～1140
7 Meade TW, Brozovic M, Haines AP, et al. Haemostatic function and ischaemic heart disease:principal results of the Northwick Park Heart study. Lancet, 1986; 2:533～538
8 Heinrich J, Balleisen L, Schulte H, et al. Fibrinogen and factorⅦ in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb, 1994; 14:54～59.
9 Ernst E. The role of fibrinogen as a cardiovasculor risk factor.Atherosclerosis, 1993;100:1～12
10 Bini A, Kudryk BJ..Fibrinogen in human atherosclerosis. Ann NY Acad Sci, 1995; 748:461～471.
11 Resch KL, Ernst E, Matrai A, et al. Fibrinogen and viscosity as risk factor for subsequent cardiovascular events in stroke survivors. Ann Intern Med, 1998; 19:634～636
12 Kannel WB, Wolf PA, Sweetnam WP, et al. Fibrinogen and risk of cardiovascular disease:the Framingham Study.J AMA, 1987; 258: 1183～1186.
13 Qizilbash N, Jones L, Warlow C, et al. Fibrinogen and lipid concentrations as risk factors for transient ischaemie attacks and minor ischaemic strokes. BMJ, 1991; 303:605～609
14 Johanna C, Moniek PM, Michiel L, et al. Elevated Plasma Fibrinogen. Arterioscler Thromb Vasc Biol, 1998; 18:621～625
15 Fey GH, Fuller GM. Regulation of acute phase gene expression by inflammatory mediators.Mol Biol Med,1987;4:323～338
16 Balleisen L, Bailey J, Epping PH, et al. Epidemiology study on factor Ⅶ factorⅧ and fibrinogen in an industrial population: Baseline data on the relation to age, gender, body weight, smoking,alcohol, pill using and menopause. Thromb Haemostas, 1985;54:475～479
17 Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other charcteristics on clotting factors and risk of ischemic heart disease. Lancet, 1987; 2:986～988
18 Hamsten A, Iselius L, de Faire U, et al. Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet, 1987; 2:988～991
19 Erika TB, Gerald MF. Detection of aComplex That Associates With the Bβ Fibrinogen G-455A Polymorphism. Blood, 1998;9 2(9):3286～3293
20 Ferdinand M, Sara JF, Silveira A, et al. Two Common, Functional Polymorphisms in the Promoter Region of the β-Fibrinogen Gene Contribute to Regulation of Plasma Fibrinogen Concentration. ArtefiosclerThrombVasc Biol,1999;19:3063～3069
21 刘蓉，李家增，穆红，等．纤维蛋白原基因多态性与缺血性心脑血管病的关系．中华血液学杂志，2002：23(9)：453456
22 Schmidt H, Schmidt R, Niederkorn K, et al. Beta-fibrinogen gene polymorphism (C148-T) is associated with carotid atherosclerosis:
results of the Austrian Stroke Prevention Study. Arterioscler Thromb Vasc Biol, 1998; 18(3):487-492
23 Blake GJ, Schmitz C, Lindpaintner K, et al..Mutation in the beta- fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis. Eur Heart J, 2001; 22(24):2262-2266
24 Green F, Hamsten A, Blomback M, et al. The role of β-fibrinogen genotype in determining plasma fibrinogen levels in young survors of myocardial infarction and healthy controls from Sweden. Thromb-Haemost, 1993;70:915-920
25 Humphrie SE, Ye S, Talmud P, et al. Europe atherosclerosis research study: genotype at the fibrinogen locus(G-445A-β-gene) is associatedwith differences in plasma fibrinogen levels in young men and women from different regions in Europe. Arterioscler Thromb Vasc Biol,1995; 15:96～104
26 Nishiuma S, Kario K, Yakushijin K, et al. Genetic variation in the promoter region of the beta-fibrinogen gene is associated with ischemic stroke in a Japanses population. Blood Coagul Fibrinolysis, 1998; 9:373～379
27 刘国勋，李凤芹，蔡望伟，等．201名广东籍人β-FBG-455G／A基因多态性分析及与血浆纤维蛋白原水平的关系．中华血液学杂志，1999：20：255～257
28 邝宇，蔡望伟，刘国勋，等．海南黎族人β-纤维蛋白原基因455G／A基因多态性的初步研究．中华医学遗传学杂志，2000：17(6)：443～444
29 Tybjaerg HA, Agerholm LB, Humphries, SE, et al. A commom mutation (G-455-A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemicheart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study. J-Clin-Invest, 1997; 99(12):3034～3039
30 Humphrie SE, Ye S, Talmud P, et al. Europe atherosclerosis research study:genotype at the fibrinogen locus(G-445A-β-gene) is associated
with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Arterioscler Thromb Vasc Bioi, 1995;15:96～104
31 马会利，陈纪林．冠心病及健康男女B HaeⅢ多态性与血浆纤维蛋白原浓度比较．临床心血管病杂志，2000：16(1)：32～34
32 赵书平，张俊洁，尤建，等．一种碘化钾提取外周血基因组DNA的方法．中华医学遗传学杂志，1999；16(6)：395～6。
33 Pencz M, Soloweiwjczyk D, Harpel B, et al. Construction of human genelibraries from small amounts of peripheral blood. Hemoglobin, 1982;6(1):27～36
34 周郁，余伍忠，滕葵，等．尿素用于DNA提取．中华医学检验杂志，1993：16(6)： 349～350
35 Loparev VN, Cartas MA, Monken CE, et al. An efficient and simple method of DNA extractionfrom whole blood and cell line to identify infectious agents. J Virolo Methods, 1992; 34(1):105～112
36 Kejnovsky E, Kypr J..DNAextraction by zinc. Nucleic Acids Res, 1997; 25:1870～1871
37 孔宪明．冠状动脉粥样硬化性疾病与血栓．见：孔宪明，高海青，张筱主编．心脏血栓病学(第一版)．北京：人民卫生出版社，2000：598～612
38 Bradley WA, Booyse FM, Giantarco SH, et al. Fibrinolytic and thrombotic factors in atherosclerosis and IHD: the influence of triglyceride rich lipoprotein(JGRLP). Atherosclerosis, 1994; 108(suppl):s31～s39
39 王雪青，刘乃奎，董林旺，等．纤维蛋白原在动脉粥样硬化中发生的作用．中国病理生理杂志，1997：13(3)：270～273
40 陈晓春，黄春，蓝玉福，等．纤维蛋白原对内皮细胞t-PA和PAI-lmRNA表达的影响．中华内科杂志，2000：39(5)：305～308
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52 Adult Treatment Panel Ⅲ. Circulation , 2002; 106:3143～3421
53 Angela M, Michale W, Max H, et al. β-Fibrinogen gene -455G/A polymorphism and fibrinogen levels risk factors for coronary artery disease in subjects with NIDDM. Diabetes Care, 1996;19(11) :165～1268
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2 吴兆苏，姚崇华，赵冬，等．我国多省市心血管病趋势及决定因素的人群监测(中国MONICA方案)．中华心血管病杂志，1997；25(1)6～11
3 国家“八五”攻关心脑血管病高发社区人群综合性预防研究课题协作组：心脑血管病社区人群综合性预防研究．中华预防医学杂志，1998，2(增刊)：3
4 吴锡桂，顾东风，李世绰，等．社区人群干预对心脑血管疾病危险因素水平的影响．中华预防医学杂志，1998，2(增刊)：16
5 洪震，黄茂盛，周玢，等．上海市静安区社区人群心脑血管病综合防治及其效果．中华预防医学杂志，1998，2(增刊)：39
6 Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med, 1984;310:1137～1140
7 Meade TW, Brozovic M, Haines AP, et al. Haemostatic function and ischaemic heart disease:principal results of the Northwick Park Heart study. Lancet, 1986; 2:533～538
8 Heinrich J, Balleisen L, Schulte H, et al. Fibrinogen and factorⅦ in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb, 1994; 14:54～59.
9 Ernst E. The role of fibrinogen as a cardiovasculor risk factor.Atherosclerosis, 1993;100:1～12
10 Bini A, Kudryk BJ..Fibrinogen in human atherosclerosis. Ann NY Acad Sci, 1995; 748:461～471.
11 Resch KL, Ernst E, Matrai A, et al. Fibrinogen and viscosity as risk factor for subsequent cardiovascular events in stroke survivors. Ann Intern Med, 1998; 19:634～636
12 Kannel WB, Wolf PA, Sweetnam WP, et al. Fibrinogen and risk of cardiovascular disease:the Framingham Study.J AMA, 1987; 258: 1183～1186.
13 Qizilbash N, Jones L, Warlow C, et al. Fibrinogen and lipid concentrations as risk factors for transient ischaemie attacks and minor ischaemic strokes. BMJ, 1991; 303:605～609
14 Johanna C, Moniek PM, Michiel L, et al. Elevated Plasma Fibrinogen. Arterioscler Thromb Vasc Biol, 1998; 18:621～625
15 Fey GH, Fuller GM. Regulation of acute phase gene expression by inflammatory mediators.Mol Biol Med,1987;4:323～338
16 Balleisen L, Bailey J, Epping PH, et al. Epidemiology study on factor Ⅶ factorⅧ and fibrinogen in an industrial population: Baseline data on the relation to age, gender, body weight, smoking,alcohol, pill using and menopause. Thromb Haemostas, 1985;54:475～479
17 Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other charcteristics on clotting factors and risk of ischemic heart disease. Lancet, 1987; 2:986～988
18 Hamsten A, Iselius L, de Faire U, et al. Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet, 1987; 2:988～991
19 Erika TB, Gerald MF. Detection of aComplex That Associates With the Bβ Fibrinogen G-455A Polymorphism. Blood, 1998;9 2(9):3286～3293
20 Ferdinand M, Sara JF, Silveira A, et al. Two Common, Functional Polymorphisms in the Promoter Region of the β-Fibrinogen Gene Contribute to Regulation of Plasma Fibrinogen Concentration. ArtefiosclerThrombVasc Biol,1999;19:3063～3069
21 刘蓉，李家增，穆红，等．纤维蛋白原基因多态性与缺血性心脑血管病的关系．中华血液学杂志，2002：23(9)：453456
22 Schmidt H, Schmidt R, Niederkorn K, et al. Beta-fibrinogen gene polymorphism (C148-T) is associated with carotid atherosclerosis:
results of the Austrian Stroke Prevention Study. Arterioscler Thromb Vasc Biol, 1998; 18(3):487-492
23 Blake GJ, Schmitz C, Lindpaintner K, et al..Mutation in the beta- fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis. Eur Heart J, 2001; 22(24):2262-2266
24 Green F, Hamsten A, Blomback M, et al. The role of β-fibrinogen genotype in determining plasma fibrinogen levels in young survors of myocardial infarction and healthy controls from Sweden. Thromb-Haemost, 1993;70:915-920
25 Humphrie SE, Ye S, Talmud P, et al. Europe atherosclerosis research study: genotype at the fibrinogen locus(G-445A-β-gene) is associatedwith differences in plasma fibrinogen levels in young men and women from different regions in Europe. Arterioscler Thromb Vasc Biol,1995; 15:96～104
26 Nishiuma S, Kario K, Yakushijin K, et al. Genetic variation in the promoter region of the beta-fibrinogen gene is associated with ischemic stroke in a Japanses population. Blood Coagul Fibrinolysis, 1998; 9:373～379
27 刘国勋，李凤芹，蔡望伟，等．201名广东籍人β-FBG-455G／A基因多态性分析及与血浆纤维蛋白原水平的关系．中华血液学杂志，1999：20：255～257
28 邝宇，蔡望伟，刘国勋，等．海南黎族人β-纤维蛋白原基因455G／A基因多态性的初步研究．中华医学遗传学杂志，2000：17(6)：443～444
29 Tybjaerg HA, Agerholm LB, Humphries, SE, et al. A commom mutation (G-455-A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemicheart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study. J-Clin-Invest, 1997; 99(12):3034～3039
30 Humphrie SE, Ye S, Talmud P, et al. Europe atherosclerosis research study:genotype at the fibrinogen locus(G-445A-β-gene) is associated
with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Arterioscler Thromb Vasc Bioi, 1995;15:96～104
31 马会利，陈纪林．冠心病及健康男女B HaeⅢ多态性与血浆纤维蛋白原浓度比较．临床心血管病杂志，2000：16(1)：32～34
32 赵书平，张俊洁，尤建，等．一种碘化钾提取外周血基因组DNA的方法．中华医学遗传学杂志，1999；16(6)：395～6。
33 Pencz M, Soloweiwjczyk D, Harpel B, et al. Construction of human genelibraries from small amounts of peripheral blood. Hemoglobin, 1982;6(1):27～36
34 周郁，余伍忠，滕葵，等．尿素用于DNA提取．中华医学检验杂志，1993：16(6)： 349～350
35 Loparev VN, Cartas MA, Monken CE, et al. An efficient and simple method of DNA extractionfrom whole blood and cell line to identify infectious agents. J Virolo Methods, 1992; 34(1):105～112
36 Kejnovsky E, Kypr J..DNAextraction by zinc. Nucleic Acids Res, 1997; 25:1870～1871
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