| Chapter 1 Association between Angiotensin-Converting Enzyme Gene,Coagulation FactorsⅦGene,apolipoprotein E(ApoE) gene and Plasminogen activator inhibitor-1 gene Polymorphisms with Blood Stasis Syndrome in Coronary Heart Disease PedigreesBackground:CHD was a multifactorial and multigenic disease and influenced by both environmental and genetic factors.During the produce and development of CHD,the insertion/deletion polymorphism of the Angiotensin converting enzyme(ACE)gene being proved to be related to the vessel endothelium functions,the apolipoprotein E(ApoE) gene being proved to be related to the mechanisms of serum lipids,coagulation factorsⅦ(FⅦ) gene being proved to be related to the function disorders of coagulation and Plasminogen activator inhibitor-1 gene Polymorphisms.they play important role.The heart blood stasis syndrome is one of the commonest syndrome,ApoE,FⅦ,ACE and PAI-1 gene polymorphism were probably the genetic marker of HBSS in CHDP.Objective:To learn the distributions of ACE,FⅦ,ApoE,PAI-1 in Hunan Province of China and to find the relationships between polymorphisms of ACE,FⅦApoE,PAI-1 gene with HBSS in CHDP and to study the effect of susceptibility with HBSS in CHDP.Methods:This was a case-control study,which enrolled 25 CHDP with HBSS,15 CHDP with non- HBSS and 10 pedigrees without CHD.PCR and PCR-RFLP techniques were performed to determine the genotypes of ACE,FⅦ,ApoE gene.PCR-VNTR techniques were performed to determine the genotypes of PAI-1 gene. Conditional Logistic regression was used to analyze the affected pedigree-member method(APM),which is analyzed by unvariable conditional Logistic regression and multiple Conditional Logistic regression after adjusting effects of traditional risk factors of CHD.After showing that the polymorphism of ACE,FⅦ,ApoE,PAI-1 gene are associated with CHD,the haplotype-based haploytpe relative risk(HHRR) and the transmission/disequilibrium test(TDT) are used to prove whether the gene is associated or linked with HBSS in CHD in Chinese Hunan han nation population.Results:1.In Hunan Province of China,the ACE I/D genotyped distribution was DD 12.50%,ID 12.50%andⅡ39.29%,respectively in parents and was DD 14.29%,ID 53.57%,Ⅱ32.14%,respectively in parents;Allele frequencies for D and I were 36.61%,63.39%,respectively in patients and D and I were 41.07%,58.93%.Allele frequencies of FⅦM1 gene were 78.57%in parents and were 85.71%in patients;the ApoE genotype distribution was E2/3 8.93%,E2/4 10.71%,E3/353.57%,E3/4 23.21%,E4/4 3.58%,respectively in parents and E2/3 14.29%,E2/4 7.14%,E3/3 67.86%,E3/4 10.71%,E4/4 0%, respectively in patients;Allele frequencies forε2,ε3,ε4 were 9.82%,69.64%,20.54%,respectively in parents and were 10.71%,80.36%,8.93%in patients.。2.In the haplotype-based haploytpe relative risk(HHRR),ACE gene D allele is not associated with HBSS in CHD;FⅦgene M1 allele,ApoE geneε4 allele and PAI-1 gene CA18 allele are associated with HBSS in CHD.3.In the transmission/disequilibrium test(TDT),ACE gene D allele and FⅦgene M1 allele are not linked with susceptibility location of HBSS in CHD.ApoE geneε4 allele and PAI-1 gene CA18 allele are linked with susceptibility location of HBSS in CHD,which might be associated or linked with HBSS in CHD in Chinese Hunan han nation population.4.In the affected pedigree-member method(APM),There were no difference in any genotype and allele frequencies of both ACE and FⅦgenes. There were significant difference in ApoE geneε4 allele and PAI-1 gene CA18 allele.Conclusions:1.There were no significant difference in genotype distribution and allele frequencies of ACE,FⅦ,ApoE,PAI-1 gene in Hunan people compared with Chinese people.2.ACE gene D allele is not associated with HBSS in CHD;FⅦgene M1 allele,ApoE geneε4 allele and PAI-1 gene CA18 allele are associated with HBSS in CHD.ApoE-ε4 allele was independent risk factor for the HBSS in CHD.3.ACE gene D allele and FⅦgene M1 allele are not linked with susceptibility location of HBSS in CHD.ApoE geneε4 allele and PAI-1 gene CA18 allele might be associated or linked with CHD with HBSS in Chinese population.ApoE-ε4 allele and PAI-1 gene CA18 were independent risk factor for the HBSS in CHD.4.CHD with HBSS was probably a multigenic syndrome with genetic factors.Chapter 2:The study of Association between the metaboly of serum lipid,the mechanisms of coagulation,vessel cell endothelial function and Blood Stasis Syndrome in Coronary Heart Disease PedigreesBackground:Research have proved the formation of HBSS in CHD is relate with the turbulence metaboly of serum lipid,the vessel endothelium damnification, the turbulence mechanisms of coagulation and is similar to the course of pathologic physiology that the blood is being the high coagulation before thrombus,the formation of HBSS in CHD have the family assembly tendency,in which incidence of a disease is higher than the colony incidence of a disease.turbulence metaboly of serum lipid is one of the important dangerous factors in CHD,which is used as a impersonality index in distinguishing syndrome and discriminate model.The high coagulation before thrombus and the low function of plasmin are found in patients of HBSS.The formation of thrombus is the pathologic base in sluggish gas to blood stasis syndrome and weak gas to blood stasis syndrome.The vessel endothelial dysfunction may be important mechanisms in the manifestation of CHD.The heart blood stasis syndrome is one of the commonest syndrome,the turbulence metaboly of serum lipid,the vessel endothelium damnification,the turbulence mechanisms of coagulation is probably three inheritance susceptibility characteristics of HBSS in CHD. Objective:1.To iunvestigate the index on the metaboly of serum lipid,the mechanisms of coagulation and the mechanism of endothelium dysfunction,and the inheritance susceptibility relations between this index and the heart blood stasis syndrome in coronary heart disease.2.To investigate the effect on the insertion/deletion polymorphism of ACE gene on ET/NO an,the polymorphism of FⅦon FⅦc activity level and the polymorphism of PAI-1 on PAI-1 activity level.Methods:This was a case-control study,which enrolled 25 CHDP with HBSS,15 CHDP with non- HBSS and 10 pedigrees without CHD.The levels of antithrombinⅢ(ATⅢ),GMP-140,tissue-type plasminogen activator(tPA), plasminogen activator inhibitor(PAl),plasma factorⅦcoagulant activity(FⅦc),angiotensinⅡ(AgⅡ),nitrogen monoxide(NO),endothelins(ET) were tested with radioimmunoassy and chemistry method.Results:1.The levels of AgⅡof HBSS group in CHDP were significantly higher than those of none-HBSS group in CHDP and healthy group(p＜0.05 or 0.01). The levels of ET,NO,NO/ET of HBSS group were significantly lowerer than those of healthy group(p＜0.05),but no significant difference compared with none-HBSS group in CHDP.2.The level of ATⅢof HBSS group in CHDP was significantly lowerer than that of healthy group(p＜0.05 or 0.01).The levels of GMP-140,PAI of HBSS group in CHDP were significantly higher than those of none-HBSS group in CHDP and healthy group(p＜0.05 or 0.01).There was significant difference between HBSS group in CHDP and healthy control group in activator of plasminogen(tPA),but no significant difference compared with none-HBSS group in CHDP.3.The effect on the insertion/deletion polymorphism of ACE gene on ET/NO:In every group,the ET/NO levels were associated with ACE I/D polymorphism:DD＞ID＞Ⅱ.There was significant difference in people carrying genotype DD compared with carrying genotypeⅡ(p＜0.05=.4.The effect on FⅦpolymorphism on levels of FⅦc activity.The levels of FⅦc activity in people carrying genotype M1M1:HBSS group in CHDP＞none-HBSS group in CHDP＞healthy control group;But contrary to genotype M1M2.5.The effect on PAI-1 polymorphism on levels of PAI-1 activity.There was correlation between the genotypes and the plasma PAI-1 activity.The shorter the dinucleotide repeats,the higher the level of PAI-1 activity.Expecially,the higher in HBSS in CHDP,the dinucleotide repeats under 20 of CA in HBSS in CHDP was higher than non-HBSS in CHDP. Conclusions:1.There was impaired endothelium dependent vascular diastolic-systolic function in HBSS of CHDP,being as impaired endothelium dependant vascular vasorelaxation function.2.There were the function disorders of coagulation,anti-coagulation and fibrinolysis in HBSS of CHDp,the state of excessive coagulation,and deficiency fibrinolysis before thrombosis.3.There was significant difference that carrying genotype DD compared with carrying genotypeⅡin ACE gene of HBSS of CHDP,which may be important action of coronary artery spasm.4.There was high correlation between the genotypes M1M1 in FⅦgene of HBSS of CHDP and levels of FⅦc activity.5.There was high negenative correlation between the genotypes and the level of plasma PAI-1 activity.6.HBSS in CHDP is relate with the turbulence metaboly of serum lipid, the vessel endothelium damnification,the turbulence mechanisms of coagulation.
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