ACE和PAI-1基因多态性与肺心病的相关性研究
|
摘要
目的 纤维蛋白原激活剂抑制剂-1(plasminogen activator inhibitor，PAI-1)是一种单链糖蛋白，属于丝氨酸蛋白酶抑制剂家族成员。纤维蛋白溶解过程的关键步骤是纤维蛋白溶解酶原在纤维蛋白溶解酶原激活剂(plasminogen activator，PA)作用下转变为纤维蛋白溶解酶，使纤维蛋白溶解，PAI-1的主要功能是快速、有效的抑制PA，导致纤维蛋白溶解作用减弱，血栓形成。血管紧张素转化酶(angiotensin converting enzyme，ACE)是一种含锌的膜结合蛋白，属二肽羧肽酶，能使血管紧张素Ⅰ转化为血管紧张素Ⅱ，后者通过与血管、气管平滑肌的作用，引起血管、支气管收缩。临床资料表明肺心病患者多伴有高凝状态和血管紧张，本研究旨在通过对肺心病患者ACE和PAI-1基因多态性的检测，从分子水平探讨肺心病的发病机理，寻找肺心病发病的相关致病基因。
方法 应用多聚酶链反应(PCR)，检测40例正常人和60例肺心病患者ACE、PAI-1的基因型和等位基因频率。
结果 ①正常对照组ACE基因型分布为DD型10.0％，II型47.5％，ID型42.5％；肺心病组ACE基因型分布为DD型20.0％，II型36.7％，ID型43.3％。统计学分析表明两组间基因型构成、I和D等位基因频率以及DD型与非DD型构成均无显著性差异。②正常对照组PAI-1基因型分布为4G／4G型12.5％，5G／5G型15.0％，4G／5G型72.5％；肺心病组PAI-1基因型分布为4G／4G型15.0％，5G／5G型28.3％，4G／5G型56.7％。统计学分析表明两组间基因型构成、4G和5G等位基因频率以及4G／4G型与非4G／4G型构成均无显著性差异。③正常女性组中ACE基因型分布为DD型12.5％，ID型37.5％，II型50.0％，等位基因频率D型为31.2％，I型为68.8％。男性组中ACE基因型分布为DD型8.4％，ID型45.8％，II型45.8％，等位基因频率D型为31.2％，I型为68.8％。统计学分析显示两组间基因型构成、等位基因频率以及DD型与非DD型构成无显著性差异。④女性肺心病患者ACE基因型分布DD型25.9％，II型48.2％，ID型25.9％；男性肺心病患者ACE基因型分布为DD型15.1％，II型27.3％，ID型57.6％．统计学分析表明两组间基因型构成有明显差异，I／D等位基因频率以及DD型与非DD型基因型构成则无明显差异。⑤正常对照组女
中文摘要
性组PAI一1基因型分布为4G/4G型6 .2%，4G/SG型68.8%，SG/SG型
25.0环;等位基因频率4G型为40.6%，SG型为59.4%;男性组中4G/4G型
16.7写，4G/SG型75.0%，SG/SG型8.3%，等位墓因频率4G型为54.2%，SG
型为45.8%.统计学分析表明两组间基因型构成、等位墓因频率以及4G/4G型
与非4G/4G型构成均无显著性差异。⑥女性肺心病患者PAI一1墓因型分布为
4G/4G型25.9%，4G/SG型55.6%，SG/SG型18.5%;男性肺心病患者PAI一1
基因型分布为4G/4G型6.1写，4G/SG型57.6%，SG/5G型36.3%.统计学分
析表明两组间基因型构成无显著性差异，4G/SG等位基因频率有显著性差异，
4G/4G型与非4G/4G型基因型构成无显著性差异。⑦在肺心病伴有肺栓塞组
的19例患者中ACE基因DD型、ID型和11型分别为3 1 .6%、42.1%和26.3%，
等位基因频率D型为52.6%，I型为47.4%.统计学分析表明，与正常对照组基
因型构成比较无显著性差异，DD型与非DD型之间有显著性差异，D/I等位基
因频率有显著性差异。⑧在肺心病伴有肺栓塞组的19例患者中PAI一1墓因
4G/4G型、4G/SG型和SG/SG型分别为10.5%、68.4写和21.1%，等位基因频
率4G型为44.7%，SG型为55.3%.统计学分析表明，与正常对照组墓因型构
成比较、4G/4G型与非4G/4G型之间以及4G/5G等位基因频率均无显著性差
异。⑨肺心病组、DD基因型患者组和4G/4G基因型患者组的Hct值范围分别
为。.521士。.155、0.528士0.112和0.519士0.097.它们分别与对照组的Hct值
0.483士0.056进行组间均数比较，显示3组间均无统计学意义(P>0.05).
结论①ACE括入/缺失墓因多态性与肺心病无明显相关性，DD基因型不
是肺心病发病的危险因子，然而DD墓因型在肺心病组有增高的趋势。②PAI一l
4G/SG墓因多态性与肺心病无明显相关性，4G/4G基因型不是肺心病发病的危
险因子。③肺心病患者中女性ACE基因中的DD基因型有升高趋势，DD基因
型可能是女性患肺心病的危险因子。④肺心病患者中，4G等位基因可能是女性
患肺心病的危险因子。⑤DD基因型与肺心病伴肺栓塞有显著相关性，DD墓因
型和D等位基因可能是肺心病伴肺梗塞的危险因子;4G/4G基因型和4G等位
基因与肺心病伴肺栓塞无明显相关性。⑥DD基因型和4G/4G基因型患者与
正常对照组平均红细胞压积无明显相关性。
Objactive Plasminogen activator inhibitor-1 (PAI-1), a kind of glycoprotein, is a member of the SERPIN family. The important step in the progress of fibrinolysis is that tissue plasminogen activator(PA) transforms plasminogen into plasmin, the latter makes fibrin degradation. PAI-1 main function is as the fast-acting inhibitor of t-PA. This action prevents the development of fibrinolysis and makes thromsis. Angiotensin converting enzyme (ACE), membrance binding protein, is a member of peptidyl-dipeptide hydrolase. ACE transforms angiotensin I into angiotensin II. Ang II produces construction of vascular and trachea by acting on smooth muscle. The clinical studies show that most patients of chronic pulmonary heart disease(CPHD) have the syndrom of high risk blood clot and an-giotonia. We investgates the reason and relative gene of CPHD on molecular level by detecting the polymorphism of ACE gene and PAI-1 gene.
Methods The ACE and PAI-1 genotype in 40 normal subjects and 60 pateints of CPHD is detected by the polymerase chain reaction (PCR).
Results (1)In the control group t the distribution of the DD, II and ID genotypes of the ACE gene is 10. 0%,47. 5% and 42. 5%;In the study group, the distribution of the DD,II and ID genotypes of the ACE gene is 20. 0%,36. 7% and 43. 3%; These percentages in control group do not significantly differ from the study group, I/Dallele frequency and DD genotype /non- DD genotype in control group do not significantly differ from the study group. (2)In the control group, the distribution of the 4G/4G,4G/5G and 5G/5G genotypes of the PAI-1 gene is 12. 5% ,72. 5% and 15. 0%;In the study group, the distribution of the 4G/4G,4G/5G and 5G/5G genotypes of the PAI-1 gene is 15. 0%,56. 7% and 28. 3 %; These percentages in control group do not significantly differ from the study group, 4G allele frequency and 4G/4G genotype /non- 4G/4G genotype in control group do not significantly differ from the study group. (3)In the female subgroup of CPHD, the distribution of the DD,II and ID genotypes of the ACE gene is 25. 9% ,48. 2%
and 25.9%; In the male subgroup, the distribution of the DD,II and ID genotypes of the ACE gene is 15.1%,27. 3% and 57. 6%;These percentages in female subgroup significantly differ from the male subgroup, I/D allele frequency and DD genotype /non- DD genotype in female
subgroup do not significantly differ form the male subgroup. (4)In the female subgroup of CPHD, the distribution of the 4G/4G.4G/5G and 5G/5G genotypes of the PAI-1 gene is
25. 9% ,55. 6% and 18. 5%; In the male subgroup, the distribution of the 4G/4G.4G/5G and 5G/5G genotypes of the PAI-1 gene is 6. 1%, 57. 6% and 36. 3%;These percentages and 4G/4G genotype /non- 4G/4G genotype in female subgroup do not significantly differ from the male subgroup, 4G allele frequency in female subgroup significantly differ from the male subgroup. (5)In 19 subjects of patients of CPHD accompanying with pulmonary embolism, the distribution of the DD.II and ID genotypes of the ACE gene is 31. 6%,
26. 3% and 42. 1%. D/I allele frequency is 52. 6% and 47. 4%. The percentages of ACE genotypes is not significantly different in control group and subgroup, The percentages of DD genotype and non-DD genotype, the I/D alleles frequency are significant association between the two groups. (6)In 19 subjects of patients of CPHD accompanying with pulmonary embolism, the distribution of the 4G/4G,5G/5G and 4G/5G genotypes of the PAI-1 gene is 10. 5 % ,21. 1 % and 68. 4 %. 4G/5G allele frequency is 44. 7 % and 55. 3 %. The percentages of PAI-1 genotypes, the percentages of 4G/4G genotype and non-4G/4G genotype, the 4G/5G alleles frequency are not significantly different. (7)The data of mean Hct is 0. 521±0. 155, 0. 528±0. 112 and 0. 519 ± 0. 097 in the CPHD group, DD genotype subgroup and 4G/4G genotype subgroup. In the control group, the mean Hct is 0. 483 ± 0. 056. There is not significantly different in control group comparing with CPHD group, DD genotype subgroup and 4G/4G genotype subgroup.
Conclusion (1)
方法 应用多聚酶链反应(PCR)，检测40例正常人和60例肺心病患者ACE、PAI-1的基因型和等位基因频率。
结果 ①正常对照组ACE基因型分布为DD型10.0％，II型47.5％，ID型42.5％；肺心病组ACE基因型分布为DD型20.0％，II型36.7％，ID型43.3％。统计学分析表明两组间基因型构成、I和D等位基因频率以及DD型与非DD型构成均无显著性差异。②正常对照组PAI-1基因型分布为4G／4G型12.5％，5G／5G型15.0％，4G／5G型72.5％；肺心病组PAI-1基因型分布为4G／4G型15.0％，5G／5G型28.3％，4G／5G型56.7％。统计学分析表明两组间基因型构成、4G和5G等位基因频率以及4G／4G型与非4G／4G型构成均无显著性差异。③正常女性组中ACE基因型分布为DD型12.5％，ID型37.5％，II型50.0％，等位基因频率D型为31.2％，I型为68.8％。男性组中ACE基因型分布为DD型8.4％，ID型45.8％，II型45.8％，等位基因频率D型为31.2％，I型为68.8％。统计学分析显示两组间基因型构成、等位基因频率以及DD型与非DD型构成无显著性差异。④女性肺心病患者ACE基因型分布DD型25.9％，II型48.2％，ID型25.9％；男性肺心病患者ACE基因型分布为DD型15.1％，II型27.3％，ID型57.6％．统计学分析表明两组间基因型构成有明显差异，I／D等位基因频率以及DD型与非DD型基因型构成则无明显差异。⑤正常对照组女
中文摘要
性组PAI一1基因型分布为4G/4G型6 .2%，4G/SG型68.8%，SG/SG型
25.0环;等位基因频率4G型为40.6%，SG型为59.4%;男性组中4G/4G型
16.7写，4G/SG型75.0%，SG/SG型8.3%，等位墓因频率4G型为54.2%，SG
型为45.8%.统计学分析表明两组间基因型构成、等位墓因频率以及4G/4G型
与非4G/4G型构成均无显著性差异。⑥女性肺心病患者PAI一1墓因型分布为
4G/4G型25.9%，4G/SG型55.6%，SG/SG型18.5%;男性肺心病患者PAI一1
基因型分布为4G/4G型6.1写，4G/SG型57.6%，SG/5G型36.3%.统计学分
析表明两组间基因型构成无显著性差异，4G/SG等位基因频率有显著性差异，
4G/4G型与非4G/4G型基因型构成无显著性差异。⑦在肺心病伴有肺栓塞组
的19例患者中ACE基因DD型、ID型和11型分别为3 1 .6%、42.1%和26.3%，
等位基因频率D型为52.6%，I型为47.4%.统计学分析表明，与正常对照组基
因型构成比较无显著性差异，DD型与非DD型之间有显著性差异，D/I等位基
因频率有显著性差异。⑧在肺心病伴有肺栓塞组的19例患者中PAI一1墓因
4G/4G型、4G/SG型和SG/SG型分别为10.5%、68.4写和21.1%，等位基因频
率4G型为44.7%，SG型为55.3%.统计学分析表明，与正常对照组墓因型构
成比较、4G/4G型与非4G/4G型之间以及4G/5G等位基因频率均无显著性差
异。⑨肺心病组、DD基因型患者组和4G/4G基因型患者组的Hct值范围分别
为。.521士。.155、0.528士0.112和0.519士0.097.它们分别与对照组的Hct值
0.483士0.056进行组间均数比较，显示3组间均无统计学意义(P>0.05).
结论①ACE括入/缺失墓因多态性与肺心病无明显相关性，DD基因型不
是肺心病发病的危险因子，然而DD墓因型在肺心病组有增高的趋势。②PAI一l
4G/SG墓因多态性与肺心病无明显相关性，4G/4G基因型不是肺心病发病的危
险因子。③肺心病患者中女性ACE基因中的DD基因型有升高趋势，DD基因
型可能是女性患肺心病的危险因子。④肺心病患者中，4G等位基因可能是女性
患肺心病的危险因子。⑤DD基因型与肺心病伴肺栓塞有显著相关性，DD墓因
型和D等位基因可能是肺心病伴肺梗塞的危险因子;4G/4G基因型和4G等位
基因与肺心病伴肺栓塞无明显相关性。⑥DD基因型和4G/4G基因型患者与
正常对照组平均红细胞压积无明显相关性。
Objactive Plasminogen activator inhibitor-1 (PAI-1), a kind of glycoprotein, is a member of the SERPIN family. The important step in the progress of fibrinolysis is that tissue plasminogen activator(PA) transforms plasminogen into plasmin, the latter makes fibrin degradation. PAI-1 main function is as the fast-acting inhibitor of t-PA. This action prevents the development of fibrinolysis and makes thromsis. Angiotensin converting enzyme (ACE), membrance binding protein, is a member of peptidyl-dipeptide hydrolase. ACE transforms angiotensin I into angiotensin II. Ang II produces construction of vascular and trachea by acting on smooth muscle. The clinical studies show that most patients of chronic pulmonary heart disease(CPHD) have the syndrom of high risk blood clot and an-giotonia. We investgates the reason and relative gene of CPHD on molecular level by detecting the polymorphism of ACE gene and PAI-1 gene.
Methods The ACE and PAI-1 genotype in 40 normal subjects and 60 pateints of CPHD is detected by the polymerase chain reaction (PCR).
Results (1)In the control group t the distribution of the DD, II and ID genotypes of the ACE gene is 10. 0%,47. 5% and 42. 5%;In the study group, the distribution of the DD,II and ID genotypes of the ACE gene is 20. 0%,36. 7% and 43. 3%; These percentages in control group do not significantly differ from the study group, I/Dallele frequency and DD genotype /non- DD genotype in control group do not significantly differ from the study group. (2)In the control group, the distribution of the 4G/4G,4G/5G and 5G/5G genotypes of the PAI-1 gene is 12. 5% ,72. 5% and 15. 0%;In the study group, the distribution of the 4G/4G,4G/5G and 5G/5G genotypes of the PAI-1 gene is 15. 0%,56. 7% and 28. 3 %; These percentages in control group do not significantly differ from the study group, 4G allele frequency and 4G/4G genotype /non- 4G/4G genotype in control group do not significantly differ from the study group. (3)In the female subgroup of CPHD, the distribution of the DD,II and ID genotypes of the ACE gene is 25. 9% ,48. 2%
and 25.9%; In the male subgroup, the distribution of the DD,II and ID genotypes of the ACE gene is 15.1%,27. 3% and 57. 6%;These percentages in female subgroup significantly differ from the male subgroup, I/D allele frequency and DD genotype /non- DD genotype in female
subgroup do not significantly differ form the male subgroup. (4)In the female subgroup of CPHD, the distribution of the 4G/4G.4G/5G and 5G/5G genotypes of the PAI-1 gene is
25. 9% ,55. 6% and 18. 5%; In the male subgroup, the distribution of the 4G/4G.4G/5G and 5G/5G genotypes of the PAI-1 gene is 6. 1%, 57. 6% and 36. 3%;These percentages and 4G/4G genotype /non- 4G/4G genotype in female subgroup do not significantly differ from the male subgroup, 4G allele frequency in female subgroup significantly differ from the male subgroup. (5)In 19 subjects of patients of CPHD accompanying with pulmonary embolism, the distribution of the DD.II and ID genotypes of the ACE gene is 31. 6%,
26. 3% and 42. 1%. D/I allele frequency is 52. 6% and 47. 4%. The percentages of ACE genotypes is not significantly different in control group and subgroup, The percentages of DD genotype and non-DD genotype, the I/D alleles frequency are significant association between the two groups. (6)In 19 subjects of patients of CPHD accompanying with pulmonary embolism, the distribution of the 4G/4G,5G/5G and 4G/5G genotypes of the PAI-1 gene is 10. 5 % ,21. 1 % and 68. 4 %. 4G/5G allele frequency is 44. 7 % and 55. 3 %. The percentages of PAI-1 genotypes, the percentages of 4G/4G genotype and non-4G/4G genotype, the 4G/5G alleles frequency are not significantly different. (7)The data of mean Hct is 0. 521±0. 155, 0. 528±0. 112 and 0. 519 ± 0. 097 in the CPHD group, DD genotype subgroup and 4G/4G genotype subgroup. In the control group, the mean Hct is 0. 483 ± 0. 056. There is not significantly different in control group comparing with CPHD group, DD genotype subgroup and 4G/4G genotype subgroup.
Conclusion (1)
引文
1 Rigat B,Hubert C.Corvol P,et al.PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene(DCP1) .Nuel Acids Res,1990,20:1433
2 Grancha S,Estelles A,Torino G,et al.Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease.Thromb Haemost,1999,81:516
3 Tiret L,Rigat B,Visvikis S,et al.Evidence from combined segregatio and linkage a-nalysis,that a variant of angiotensin-converting enzyme gene control plasma ACE level.Am J Hum Genet,1992,51:197
4 Nakai K,Itoh C,Miura Y,et al.Deletion polymorphism of the angiotensin I-converting enzyme gene associates with increased risk for ischemic heart diseases in the Japanese.Rinsho Byori,1994,42:689
5 侯淑琴，郑华青，周文郁，等．血压患者血管紧张素转化酶基因多态性分析．基础医学与临床，1999，19：25
6 Lindpaintne K,Lee M,Larson MG,et al.Absence of association of geneic linkage be-teen the angiotensin converting enzymegene and left ventricular mass.N Engl J Med,1996,334:1023
7 Higashimori K,Zhao Y,Higaki J,et al.Assciation analysis of a polymorphism of the angiotensin-converting enzyme gene with essential hypertension in the Japanese population.Biochem Res Commum,1993,191:399
8 Hong SK,Kang BY,Park W H,et al.Genetic variation of the angiotensin-converting enzyme gene:increased frequency of the insertion allele in Korenans.Clin Genet,1997,51:35
9 Gambien F,Poirier O,Lecerf L.Deletion polymorphism in the gene angiotensin-converting enzyme is a risk factor for myocardial infarction.Nature,1992,359:641
10 Hibi D,Ishigami T,Kimura k,et al.Angiotensin-converting enzyme gene polymorphism adds risk for the severity of coronary atherosclerosis in smokers.Hypertension,1997,30:574
11 Isbir T,Yilmaz H,Agachan B,et al.Association between angiotensin-converting enzyme gene polymorphism and coronary artery disease.Iubmb Life,1999,48:205
12 杨 MIN．血管紧张素转化酶基因的多态性与心血管疾病的关系．心脏杂志，2001，13：58
13 Hernandez Ortega E,Medina Fernandez-Aceituno A,Rodriguez Esparragon FJ,et al.
The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease. Rev Esp Cardiol, 2002, 55:89
14 Van B,Ockxmeer FM, Mamotte CD,et al. Angiotensin-converting enzyme gene polymorphism and premature coronary heart disease. Clin Sci (Lond), 2000, 99:247
15 叶琼，吴可贵，谢良地，等．血管紧张素原及血管紧张素转化酶基因多态性与高血压之间的关系．中华医学遗传学杂志，2000，17：28
16 周雪艳，杨海淼，窦铁华．血管紧张素转换酶基因多态性与原发性高血压的关系．中国老年学杂志，2000，20
17 Harrap SB,Daviddson HR,Connor JM,et al. The angiotensin-converting enzyme gene and predisposition to high blood pressure. Dutchhypertension and offspring study. J Hypertens, 1993,11: 345
18 Morise T,Takeuchi Y,Takeda R. Angiotensin-converfing enzyme polymorphism and essential hypertension. Lancet,1994,343: 125
19 Zee RYL,Lo Y,Griffiths LR,et al. Association of the the angiotensin converting enzyme gene with essental hypertension. Biochem Biophy Res Comrnun,1992,184:9
20 Duru K, Farrow S, Wang JM, et al. Frequency of a deletion polymorphism in the gene for angiotensin converting enzyme is increased in African-Americans with hypertension. Am J Hypertens,1994, 7: 759
21 郭胜祥，张洪玉，翁心植，等．老年肺心病患者吸入一氧化氮后血流动力学与血管调节因子的变化．中华老年医学杂志，1991，5：133
22 Morrel N, Atochina KG, Morrs SM,et al. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxiainduced pulmonary hypertension. J Clin Invest, 1995,96:1823
23 Hiroski K, Takashi O,Kazuto H,et al. Deletion polymorphism in the angiotensin-converting enzyme gene are associated pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease. Am J Res Crit Care Med,2000,162: 1235
24 Aldashev AA, Sarybaev AS,Sydykov AS,et al. Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med, 2002, 15:166
25 Robert J, Van S,Emiel F,ct al. The DD genotype of the angiotensin-converting enzyme gene is negatively association with right ventricular hypertrophy in male patients with chronic obstructive pulmonary. Am J Res Grit Care Med,1999,159: 1791
26 Abraham W, Raynolds M,Gottschall B,et al. Importance of angiotensin-converting enzyme in pulmonary hypertension. Cardiology, 1995,86:9
27 Lu Y, Hui R, Zhao Y. Insertion/deletion polymorphsim of the angiotensin Ⅰ conver
ting enzyme gene and pulmonary thromboembolism in Chinese opulation. Zhong hua Jie He He Hu Xi Za Zhi, 2001, 24(2)
28 Margaglione M, Grandone E, Vecchione G, et al. Plasminogen activator inhibitor-1 (PAI-1) antigen plasma level in subjects attending a metabolic ward: relation to polymorphism of PAI-1 and angiotensin-converting enzyme gene. Arterioscler Thromb Vasc Biol, 1997,17:2082
29 Mansfield MW,Stickland MH,Grant PJ. Enviromental and genetic factors in relation to elevated circulating levels of the plasminogen activator inhibitor-1 in caucasian patients with non-insulin-depended diabet mellitus. Thromb Haemost, 1995,74: 842
30 Kimura H,Gejyo F, Suzuki Y,et al. Polymorphsim of the angiotensin Ⅰ converting enzyme geneand plasminogen activator inhibitor-1 in diabetes and macroangiopathy. Kidney International, 1998,54:1659
31 Eriksson P, Kallin B, Hooft FM, et al. Allele-specific associated with myocardial infarction. Proc Natl Acad Sci U S A, 1995,92: 1851
32 Gardemann A, Lohre J, Katz N,et al. The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost, 1999,82:1121
33 Ye S, Green FR, Scarabin PY, et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost, 1995,74:837
34 王虹，张京岚．慢性肺心病急性期血栓前状态相关指标的临床观测．中国实用内科学杂志，1999，19：286
35 金振钟．肺源性心脏病患者血浆纤溶酶原激活物抑制物-1的实验研究．国外医学·心血管疾病分册，1998，25：350
36 Ridker PM,Hennekens CH,Lindpaintner K, et al. Arterial and venous thrombosis is not associated with the 4G/5G po]ymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation,1997,95:59
37 富路，孔一慧，李佳等．纤溶酶原激活剂抑制剂-1基因启动子区4G／5G多态性与血栓性疾病的相关性研究．中华心血管病杂志，2001，29：144
38 Reilly CF,Fujita T,Mayer EJ,et al. Both circulating and clot-bound plasminogen activator inhibitor-1 (PAI-1) inhibter endogenous fibrinolysis in the rat. Arteriosclar Thromb, 1991,11: 1276
39 Stegnar M, Uhrin P,Peternel P,et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thrombolsrn. Thromb Haemost, 1998,79: 975
2 Grancha S,Estelles A,Torino G,et al.Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease.Thromb Haemost,1999,81:516
3 Tiret L,Rigat B,Visvikis S,et al.Evidence from combined segregatio and linkage a-nalysis,that a variant of angiotensin-converting enzyme gene control plasma ACE level.Am J Hum Genet,1992,51:197
4 Nakai K,Itoh C,Miura Y,et al.Deletion polymorphism of the angiotensin I-converting enzyme gene associates with increased risk for ischemic heart diseases in the Japanese.Rinsho Byori,1994,42:689
5 侯淑琴，郑华青，周文郁，等．血压患者血管紧张素转化酶基因多态性分析．基础医学与临床，1999，19：25
6 Lindpaintne K,Lee M,Larson MG,et al.Absence of association of geneic linkage be-teen the angiotensin converting enzymegene and left ventricular mass.N Engl J Med,1996,334:1023
7 Higashimori K,Zhao Y,Higaki J,et al.Assciation analysis of a polymorphism of the angiotensin-converting enzyme gene with essential hypertension in the Japanese population.Biochem Res Commum,1993,191:399
8 Hong SK,Kang BY,Park W H,et al.Genetic variation of the angiotensin-converting enzyme gene:increased frequency of the insertion allele in Korenans.Clin Genet,1997,51:35
9 Gambien F,Poirier O,Lecerf L.Deletion polymorphism in the gene angiotensin-converting enzyme is a risk factor for myocardial infarction.Nature,1992,359:641
10 Hibi D,Ishigami T,Kimura k,et al.Angiotensin-converting enzyme gene polymorphism adds risk for the severity of coronary atherosclerosis in smokers.Hypertension,1997,30:574
11 Isbir T,Yilmaz H,Agachan B,et al.Association between angiotensin-converting enzyme gene polymorphism and coronary artery disease.Iubmb Life,1999,48:205
12 杨 MIN．血管紧张素转化酶基因的多态性与心血管疾病的关系．心脏杂志，2001，13：58
13 Hernandez Ortega E,Medina Fernandez-Aceituno A,Rodriguez Esparragon FJ,et al.
The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease. Rev Esp Cardiol, 2002, 55:89
14 Van B,Ockxmeer FM, Mamotte CD,et al. Angiotensin-converting enzyme gene polymorphism and premature coronary heart disease. Clin Sci (Lond), 2000, 99:247
15 叶琼，吴可贵，谢良地，等．血管紧张素原及血管紧张素转化酶基因多态性与高血压之间的关系．中华医学遗传学杂志，2000，17：28
16 周雪艳，杨海淼，窦铁华．血管紧张素转换酶基因多态性与原发性高血压的关系．中国老年学杂志，2000，20
17 Harrap SB,Daviddson HR,Connor JM,et al. The angiotensin-converting enzyme gene and predisposition to high blood pressure. Dutchhypertension and offspring study. J Hypertens, 1993,11: 345
18 Morise T,Takeuchi Y,Takeda R. Angiotensin-converfing enzyme polymorphism and essential hypertension. Lancet,1994,343: 125
19 Zee RYL,Lo Y,Griffiths LR,et al. Association of the the angiotensin converting enzyme gene with essental hypertension. Biochem Biophy Res Comrnun,1992,184:9
20 Duru K, Farrow S, Wang JM, et al. Frequency of a deletion polymorphism in the gene for angiotensin converting enzyme is increased in African-Americans with hypertension. Am J Hypertens,1994, 7: 759
21 郭胜祥，张洪玉，翁心植，等．老年肺心病患者吸入一氧化氮后血流动力学与血管调节因子的变化．中华老年医学杂志，1991，5：133
22 Morrel N, Atochina KG, Morrs SM,et al. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxiainduced pulmonary hypertension. J Clin Invest, 1995,96:1823
23 Hiroski K, Takashi O,Kazuto H,et al. Deletion polymorphism in the angiotensin-converting enzyme gene are associated pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease. Am J Res Crit Care Med,2000,162: 1235
24 Aldashev AA, Sarybaev AS,Sydykov AS,et al. Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med, 2002, 15:166
25 Robert J, Van S,Emiel F,ct al. The DD genotype of the angiotensin-converting enzyme gene is negatively association with right ventricular hypertrophy in male patients with chronic obstructive pulmonary. Am J Res Grit Care Med,1999,159: 1791
26 Abraham W, Raynolds M,Gottschall B,et al. Importance of angiotensin-converting enzyme in pulmonary hypertension. Cardiology, 1995,86:9
27 Lu Y, Hui R, Zhao Y. Insertion/deletion polymorphsim of the angiotensin Ⅰ conver
ting enzyme gene and pulmonary thromboembolism in Chinese opulation. Zhong hua Jie He He Hu Xi Za Zhi, 2001, 24(2)
28 Margaglione M, Grandone E, Vecchione G, et al. Plasminogen activator inhibitor-1 (PAI-1) antigen plasma level in subjects attending a metabolic ward: relation to polymorphism of PAI-1 and angiotensin-converting enzyme gene. Arterioscler Thromb Vasc Biol, 1997,17:2082
29 Mansfield MW,Stickland MH,Grant PJ. Enviromental and genetic factors in relation to elevated circulating levels of the plasminogen activator inhibitor-1 in caucasian patients with non-insulin-depended diabet mellitus. Thromb Haemost, 1995,74: 842
30 Kimura H,Gejyo F, Suzuki Y,et al. Polymorphsim of the angiotensin Ⅰ converting enzyme geneand plasminogen activator inhibitor-1 in diabetes and macroangiopathy. Kidney International, 1998,54:1659
31 Eriksson P, Kallin B, Hooft FM, et al. Allele-specific associated with myocardial infarction. Proc Natl Acad Sci U S A, 1995,92: 1851
32 Gardemann A, Lohre J, Katz N,et al. The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost, 1999,82:1121
33 Ye S, Green FR, Scarabin PY, et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost, 1995,74:837
34 王虹，张京岚．慢性肺心病急性期血栓前状态相关指标的临床观测．中国实用内科学杂志，1999，19：286
35 金振钟．肺源性心脏病患者血浆纤溶酶原激活物抑制物-1的实验研究．国外医学·心血管疾病分册，1998，25：350
36 Ridker PM,Hennekens CH,Lindpaintner K, et al. Arterial and venous thrombosis is not associated with the 4G/5G po]ymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation,1997,95:59
37 富路，孔一慧，李佳等．纤溶酶原激活剂抑制剂-1基因启动子区4G／5G多态性与血栓性疾病的相关性研究．中华心血管病杂志，2001，29：144
38 Reilly CF,Fujita T,Mayer EJ,et al. Both circulating and clot-bound plasminogen activator inhibitor-1 (PAI-1) inhibter endogenous fibrinolysis in the rat. Arteriosclar Thromb, 1991,11: 1276
39 Stegnar M, Uhrin P,Peternel P,et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thrombolsrn. Thromb Haemost, 1998,79: 975