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1、Gene Polymorphisms and Coronary Heart DiseaseFang ZhengClinic Lab, Zhongnan Hospital,Wuhan UniversityCoronary Heart Disease is still the No. 1 killer in the world.GeneticsEnvironmentalLife styleThe prevention of CHD is based on the control of several factors associated with a disease or clinical con
2、dition and suspected to play a pathogenetical role, defined as risk factors.The risk factors of CHD included:AgeClotting factorsSex Fibrinolytic factors Hypertension Hyperhomocysteinaemia SmokingInflammation factorsDiabetesEndothelium factorHyperlipidaemia Nutrition factorObesity Post-menopausal sta
3、tus Genetic factorsEmerged CHD Risk FactorsBut 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 be
4、longing 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. Whats normal polymorphism?The occurrence in a popul
5、ation (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 th
6、an can be accounted for by mutation alone. Polymorphism and MutationThey are both single nucleotide poly- morphism，SNP.npolymorphismnormal phenotypenmutationdiseasenpolymorphismmorenmutation lessCardiovascular disease is complex as a consequence of pleiotropy. These included environmental and geneti
7、cs 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.1. The gene polymorphisms as independent risk predictorsnAn HphI polymorphism in the E-selectin gene is asso
8、ciated with premature coronary artery disease.nApoE gene polymorphism is related to coronary heart disease.nE23K polymorphism in KCNJ11 gene has relationships with coronary heart disease.Every gene variants that contribute to CHD like tiny weights in balance.E-selectin belongs to a family of structu
9、rally 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 l
10、esion 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 CHDThe transversion of G98T mutation abolishes the HphI recognition site.NT 92 TTGGGTGAAAAG103NT 92 TTGGGTTAAAAG10
11、3HphIHphIbp332 194138Kb 1.35 0.630.31 0.19 0.12The PCR product was digested by HphI and separated on 2 % agarose gel electrophoresis. PCR amplification of the genomic DNA, subcloning and DNA sequencing were carried out. 9898GG genotype:TT genotype:Table Frequency of the E-selectin G98T mutation in t
12、he 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 ana
13、lysis 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 populationa Control 71 128 (90.14) 14 (10.93) 142 CAD 93 160 (8
14、6.02) 26 (13.98) 186 P b NS The subsetc: Control 50 90 (90.00) 10 (10.00) 100 CAD 51 80 (78.43) 22d (21.57) 102Pb 0.05)The concentrations of C-reactive protein in different genotype groups Gene typen CRP medianInter-quartile rangeCC121 2.05 *0.67-3.64 *CT93.98 1.69-6.68* (P0.05) The Taqpolymorphism
15、of IL-1 was associated with the concentrations of CRP in normal peoplen The Taqpolymorphism of IL-1 was not associated with with CHD nCRP, The first acute-phase protein to be described, its plasma concentration increases during inflammatory states.nRecently, CRP might have an important role in the pathogenesis and prediction of CHD.1.7 CRP gene and CHDnPolymorphism analysisFigure 1-1 Determination of the +1444 C/T poly
