基因多态性与冠心病课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Gene Polymorphisms and Coronary Heart Disease,Fang Zheng,Clinic Lab, Zhongnan Hospital,Wuhan University,Gene Polymorphisms and Coronar,Coronary Heart Disease is still the No. 1 killer in the world.,Coronary Heart Disease is stil,Genetics,Environmental,Life style,The prevention of CHD is based on the control of several factors associated with a disease or clinical condition and suspected to play a pathogenetical role, defined as risk factors.The risk factors of CHD included:,GeneticsEnvironmentalLife styl,Age,Clotting factors,Sex,Fibrinolytic factors,Hypertension,Hyperhomocysteinaemia,Smoking,Inflammation,factors,Diabetes,Endothelium factor,Hyperlipidaemia,Nutrition factor,Obesity,Post-menopausal status,Genetic factors,Emerged CHD Risk Factors,AgeClotting factorsSex Fibrino,But only in 5% of hereditary CHD, the gene background was clear. In the others, each genetic factor played a minor role in occurrence and development of the disease.,Rare mutations (e.g., in the LDLR and APOE genes) may have a major effect, whereas genes belonging to normal polymorphism have only a moderate effect. But even genes with only a slight effect can be clinically important in combination with other genes.,The importance of polymorphism analyses will increase significantly in the near future.,But only in 5% of hereditary C,Whats normal polymorphism?,The occurrence in a population (or among populations) of several phenotypic forms associated with alleles of one gene or homologs of one chromosome. The occurrence together in the same population of more than one allele or genetic marker at the same locus with the least frequent allele or marker occurring more frequently than can be accounted for by mutation alone.,Whats normal polymorphism?The,Polymorphism and Mutation,They are both single nucleotide poly-morphism，SNP.,polymorphismnormal phenotype,mutationdisease,polymorphismmore,mutation less,Polymorphism and Mutation Th,Cardiovascular disease is,complex as a consequence of pleiotropy.,These included environmental and genetics factors. Gene polymorphism played an important role in the occurrence and development of cardiovascular disease. And it can be applied on the prediction, diagnosis, treatment and prognosis.,Cardiovascular disea,1. The gene polymorphisms as independent risk predictors,An HphI polymorphism in the E-selectin gene is associated with premature coronary artery disease.,ApoE gene polymorphism is related to coronary heart disease.,E23K polymorphism in KCNJ11 gene has relationships with coronary heart disease.,1. The gene polymorphisms as,Every gene variants that contribute to CHD like tiny weights in balance.,Every gene variants that contr,E-selectin belongs to a family of structurally related selectin molecules including E-, P- and L-selectin and participates in the endothelial-leukocyte adhesion .,Experiments using E-and P-selectin-double-knockout mice suggest that E- and P-selectin together play an important role in both early and advanced stages of the atherosclerotic lesion development.,Several polymorphisms in the E-selectin gene have been identified as new risk factors for the early atherosclerosis.,1.1 The G98/T polymorphism in E-selectin gene and CHD,E-selectin belongs to a,The transversion of G98,T mutation abolishes the,Hph,I recognition site.,NT 92 TTG,GGT,G,A,AAAG103,NT 92 TTG,GGT,T,A,AAAG103,Hph,I,Hph,I,The transversion of G98T muta,bp,332,194,138,Kb,1.35,0.63,0.31,0.19,0.12,The PCR product was digested by HphI and separated on 2 % agarose gel electrophoresis.,bp332194138Kb1.350.630.310.190,PCR amplification of the genomic DNA, subcloning and DNA sequencing were carried out.,98,98,GG genotype:,TT genotype:,PCR amplification of the genom,Table Frequency of the E-selectin G98T mutation in the angiographically documented premature CAD and controls,(,The original population: all males aged,50 yr.old, all females aged,60 yr. old; the subset: All males aged,45 yr.old, all females aged,55 yr. old),a: In control, 32 males, 39 females; in CAD, 51 males, 42 females.,b: Chi-square statistical analysis was done using Sigma Stat (ver.2.0, SPSS Inc., Chicago, IL).,c: In control, 21 males, 29 females; in CAD, 28 males, 23 females.,d: Include 18 heterozygotes (GT) and two homozygotes (TT).,N G-allele (%) T-allele (%) Total alleles,The population,a,Control 71 128 (90.14) 14 (10.93) 142,CAD 93 160 (86.02) 26 (13.98) 186,P,b,NS,The subset,c,:,Control 50 90 (90.00) 10 (10.00) 100,CAD 51 80 (78.43) 22,d,(21.57) 102,P,b,0.05),Comparison of distribution of,The concentrations of C-reactive protein in different genotype groups,Gene type,n,CRP median,Inter-quartile range,CC,121,2.05 *,0.67,-,3.64 *,CT,9,3.98,1.69,-,6.68,*,(,P,0.05),The concentrations of C-reacti,The Taqpolymorphism of IL-1 was associated with the concentrations of CRP in normal people,The Taqpolymorphism of IL-1 was not associated with with CHD,The Taqpolymorphism of IL-1,CRP, The first acute-phase protein to be described, its plasma concentration increases during inflammatory states.,Recently, CRP might have an important role in the pathogenesis and prediction of CHD.,1.7 CRP gene and CHD,CRP, The first acute-phase pro,Polymorphism analy,sis,Figure 1-1 Determination of the +1444 C/T polymorphism in the CRP gene by PCR-RFLP.,Lane M：DNA Marker;,Lane A：PCR,product;,Lane B：homozygous CC;,Lane C：heterozygous CT;,Polymorphism analysisFigure 1-,Polymorphism analy,sis,Figure The chromatogram of homozygous CC,Polymorphism analysisFigure,Comparison of distribution of,+1444 C/T genotypes and alleles between CHD group and control group,Groups,n,Genotype Distribution(%),Allele Distribution(%),CC,CT+TT,C,T,CHD,128,114(89.1),14(10.9),242(94.5),14(5.5),Control,119,107(89.9),12(10.1),226(95.0),12(5.0),2,0.048,0.045,P,0.827,0.832,OR(95%CI),0.913(0.4042.063) *,0.918(0.4162.027),*:,genotype CC vs CT+TT；：allele C vs T,Comparison of distribution of,The concentrations of C-reactive protein in different groups,Groups,n,median,Inter-quartile range,CHD,128,1.21,0.632.58,CC,114,1.21,0.672.48,CT+TT,14,1.52,0.513.73,Control,119,0.77,0.591.22,CC,107,0.75,0.591.15,CT+TT,12,1.42,0.663.05,The concentrations of C-reacti,The,+1444 C/T polymorphism of CRP was associated with the basal concentrations of CRP in normal people.,The +1444 C/T polymorphism of CRP was not associated with CHD.,The +1444 C/T polymorphism of,1.8 Conclusion for the study on polymorphisms as predictors of CHD,We found the polymorphisms of E-selectin, ApoE gene and KCNJ11 gene were related to CHD disease.,The polymorphisms in LDL-R gene and ApoE gene effected the level of lipid.,The polymorphisms of IL-1and CRP genes influenced the CRP baseline.,We didnt find any association between polymorphism in fibronectin gene and CHD.,1.8 Conclusion for the study o,Patients with an acute myocardial infarction are of high risk to develop ischemia induced ventricular arrhythmias, leading to sudden cardiac death in about one third of all AMI patients.,The individual susceptibility to ischemia-induced arrhythmias may be modified by polymorphisms in genes encoding ion channels.,A.Jeron studied the Kir6.2 gene. Opening of the K,ATP,channel during ischemia results in action potential shortening in various studies and may therefore influence the outcome of AMI patients.,However they didnt find any significant influence of Kir6.2 gene polymorphism on the risk of SCD in patients with CHD.But they identified two novel missense mutations in a highly conserved region of the Kir6.2 gene.,2.Gene polymorphism and prognosis,Patients with an acute myocar,From:,Johnson,J. A.,TRENDS in Genetics,2019,Vol.19 No.11:660-666,3. Gene polymorphism and pharmacogenomics,From: Johnson J. A. TRENDS in,The new pharmacogenetics uses powerful experimental and data-handling techniques in DNA analysis to discover and assemble a comprehensive list of the variations within the human genome specifically, SNPs and then defines complex genetic profiles of these SNPs that predict the use of new or existing therapeutic agents with maximal efficacy and minimal toxicity.,The new pharmacogenetics uses,A genetic test for certain single nucleotide polymorphisms(SNP) will predict you that:,You should suffer a severe adverse reaction to it.,You are expected to shown an excellent response to a different medication with little chance of side effects.,This is the promise of pharmacogenetics,The optimization of drug therapy based on the individual genetic profile.,A genetic test for certain sin,The,HMG-CoA reductase is the rate-limited enzyme in the biosynthesis of cholesterol.,Statins, the,HMG-CoA reductase inhibitors, are widely designed to reduce de novo cholesterol bio,synthesis.,The,efficacy and toxicity,of Statins are different in different individuals.,For Example:,The HMG-CoA reductase is the r,Recently, investigation in the relationship of statins effects and gene polymorphisms related to the lipoprotein metabolism has been developed.,These genes included the apolipoprotein E gene, hepatic lipase gene, lipoprotein lipase gene and CETP gene.,Recently, investigation in th,In 2000,Siest G,et al used different HMG-CoA reductase inhibitors to detect the relationship of apo E polymorphisms and LDL-C level. It showed the best effects to reduce LDL-C in2 carriers.,The4 carriers has elevated level of plasma cholesterol. And the affinity of LDL particles to LDL receptor was increased, the activity of HMG-CoA reductase was decreased. The effect of statins in4 carriers was poor may be due to the low base level of HMG-CoA reductase activity.,In 2000, Siest G et al used di,In 2019, Carlquist et al had concluded that the Taq1B polymorphism in the CETP gene is associated with CETP activity, HDL concentration, atherosclerosis progression, and response to statins.,Their findings suggested, for the first time, the potential of CETP Taq1B genotyping to enable more effective, pharmacogenetically directed therapy.,In 2019, Carlquist et al had c,From:,Johnson,J. A.,TRENDS in Genetics,2019,Vol.19 No.11:660-666,From: Johnson J. A. TRENDS in,Identification of all gene variants that contribute to CHD appears possible; this may considerably improve our understanding of the aetiology and mechanisms of this disease.,Furthermore, simultaneous analysis of several predisposing alleles may help to identify high-risk individuals and assess prognosis.,And the treatment of CHD could be guided by screening certain SNP using pharamcogenetic methods.,In a word,Identification of all gene var,.,From:,Pfost,D R et al. TIBTECH, 2000 (Vol. 18):334-338,.From: Pfost D R et al. TIBT,Aknowlegement！,Aknowlegement！,Aknowlegement！,Aknowlegement！,Prof. Xin Zhou,Prof. Li Xia,Yin Zhang,Chenling Xiong,Xiaobo Sun,Aknowlegement！Aknowlegement！Ak,xiexie!,谢谢！,xiexie!谢谢！,52,