MTHFR基因C667T和A1298C多态位点和高同型半胱氨酸与冠心病的相关性研究

目的探讨亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)基因上C667T和A1298C多态位点与冠心病(coronary heart disease,CHD)的相关性,以及寻找冠心病的发病危险因素。方法随机选取行冠状动脉造影确诊的冠心病患者200例和同期同地区正常对照200例,运用Taqman方法对C667T和A1298C两个多态位点进行基因分型,罗氏生化和发光(Cobas8000)流水线来测定生化指标及血浆高同型半胱氨酸(homocysteine,HCY)、磷酯酶A2(phospholipase A2,PLA2)、血清叶酸水平等。结果冠心病组的体质量指数(body mass index,BMI)、收缩压(systolic pressure,SBP)、脂蛋白a(lipoprotein a,Lp a)、糖化血红蛋白(glycated hemoglobin,HbA1c)、磷脂酶A2、HCY水平均显著高于对照组;而总胆固醇(total cholesterol,TC)、低密度脂蛋白(LDL-C)、血清叶酸则显著低于对照组。对其进行单因素Logistic回归分析发现,除去上述变量,C667T多态位点也是冠心病发病的危险因素;进一步对C667T和A1298C两个多态位点进行分析时发现,C667T多态位点与冠心病存在相关性,冠心病组的T等位频率为39.0%,远高于对照组的22.0%(P=0.045);在显性模型中,CT/TT vs.CC的P值为0.029,OR=2.60,95%CI分别为1.03~6.14;不同基因型趋势检验P=0.016。而A1298C多态位点并未观察到其与冠心病存在相关性。在C667T和A1298C两个多态位点的联合单倍型分析中,发现只有当两个多态位点同时发生突变(T-G型)时,才存在统计学差异(P=0.034,OR=3.54,95%CI=1.10~11.41),单倍型的分布模式在病例和对照组之间有显著差异(P=0.037)。结论MTHFR基因上C667T多态位点与冠心病存在相关性,而A1298C多态位点并未观察到相关性,单倍型分析发现两者同时发生突变时可增加冠心病的发病风险。

A Correlational Study on MTHFR C667T and A1298C Gene Polymorphism and High Homocysteine and Coronary Heart Disease

Objective To explore relevance of polymorphic site of C667T and A1298C on gene of MTHFR(Methylene tetrahydrofolate reductase)and coronary heart disease(CHD)and to identify risk factors for pathogenesis of coronary heart disease.Methods 200 cases of patients with coronary heart disease that were diagnosed by coronary artery angiography and 200 cases of normal controls in the same district and during the same period were randomy selected for the study.Taqman method was used to conduct genotype on two polymorphic sites of C667T and A1298C.Roche biochemistry and luminescence assembly line(Cobas8000)were used to determine biochemical index and plasm high HCY(Homocysteine),phospholipase A2 and serum folic acid levels.Results BMI,systolic blood pressure(SBP),lipoproteinLp(a)]and glycated hemoglobin(HbA1c),as well as phospholipase A2 and HCY level of the coronary artery heart disease group were all significantly higher than that of the control group.However,total cholesterol(TC),low density lipid protein(LDL-C)and serum folic acid were significantly lower than that of the control group.Single factor logistic regression analysis found that except for variates mentioned above,polymorphic site of C667T was also risk factor for pathogenesis of coronary heart disease.When conducting analysis on two polymorphism sites on C667T and A1298C,it was found that there was relevance between C667T polymorphic site and coronary heart disease:T allelic frequency of the coronary heart disease group was 39.0%,which was much higher than 22.0%of the control group(P=0.045).In dominant model,CT/TT vs.P value of CC was 0.029,also OR value and 95%CI were 2.60 and 1.03-6.14,respectively.Different genotypes tendency test showed P=0.016.However,no relevance between A1298C polymorphic site and coronary heart disease was observed.In combined haplotype analysis on two polymorphic sites of C667T and A1298C,it was found that only when two polymorphic sites underwent mutation(T-G type)simultaneously,should statistical difference exist(P=0.034,OR=3.54,95%CI=1.10-11.41),and distribution pattern of haplotype between cases and control groups had a significant difference(P=0.037).Conclusion Relevance exists between polymorphic site of C667T on MTHFR gene and coronary heart disease,however,no relevance is observed on A1298C polymorphic site.Haplotype analysis shows that when the two sites undergo mutation simultaneously,it can increase pathogenesis risk of coronary heart disease.