摘要目的 分析中国天津地区汉族冠状动脉性心脏病(coronary heart disease,CHD)患者胆固醇酯转运蛋白(cholesteryl ester transfer protein,CETP)基因-629C/A多态性,从药物基因组学角度探讨遗传因素对于阿托伐他汀钙调脂疗效以及患者长期预后的影响,为个体化治疗提供理论依据.方法 研究对象为经冠状动脉造影检查证实的CHD患者232例.应用聚合酶链反应-限制性片段长度多态性方法检测其CETP 629C/A基因型,用酶联免疫吸附测定法(enzyme-linked immunosorbent assay,ELISA)测定血清CETP含量.所有患者接受阿托伐他汀钙20 mg/d调脂治疗1年后复查血脂,随访12～23个月,记录MACE事件(包括死亡、非致死性心肌梗死、再次血运重建和卒中).采用Kaplan-Meier生存曲线Log-rank 检验分析不同基因型对于生存率的影响.结果 A突变等位基因频率为0.475,C等位基因频率为0.525；CC、CA、AA基因型相比,血清高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)水平呈升高趋势,血清CETP水平呈降低趋势,但差异均无统计学意义(F=0.893,P=0.411;F=1.279,P=0.282).血清HDL-C水平与CETP浓度呈负向变化趋势,但其相关性无统计学意义(r=-0.151,P=0.081).阿托伐他汀钙20 mg/d调脂治疗1年后,CC基因型携带者低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平下降最多,达35.41％,CA基因型次之,为18.84％,AA基因型下降最少,为8.15％,差异有统计学意义(P=0.001).血清脂蛋白(a)水平变化在不同基因型3组间差异有统计学意义(P=0.021),CC基因型下降最明显,为30.41％；3种基因型患者HDL-C水平的变化尽管呈梯度变化的趋势,但差异无统计学意义(P=0.470)；CC基因型HDL-C水平升高最明显,为14.37％,CA基因型为10.48％,AA基因型为6.64％；对总胆固醇、甘油三酯、极低密度脂蛋白胆固醇、以及载脂蛋白ApoAI和ApoB的调节效果未受到CETP多态性的影响.随访(18.66±5.99)月,发生MACE事件18例(7.76％),其中死亡2例(0.86％),非致死性心肌梗死5例(2.16％),再次血运重建9例(3.88％),卒中2例(0.86％).3种基因型无MACE生存率分别为CC型92.4％,CA型85.3％,AA型65.0％,差异无统计学意义(Log-rank P=0.444).结论-629AA基因型患者具有较高基线HDL-C水平和较低的CETP浓度,而-629CC基因型携带者有更好的他汀类调脂效果,LDL-C和脂蛋白水平下降更明显.3种基因型患者长期临床预后无显著差异.

abstractsObjective To investigate cholesteryl ester transfer protein (CETP) gene polymorphism -629C/A among Han Chinese patients with coronary heart disease (CHD) in Tianjin region,and to assess the influence of genetic factors on therapeutic effect of atorvastatin and clinical outcome in order to provide a pharmacogenomic basis for individual treatment.Methods From October 2010 to July 2011,232 patients with angiographically confirmed CHD were recruited.Polymorphism of position-629 of the CETP gene promoter was determined with polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method.Serum level of CETP was determined with enzyme-linked immunosorbent assay (ELISA).Lipid level in all patients was determined at baseline and after 12 months of treatment with 20 mg/d atorvastatin.Clinical follow-up was carried out for more than a year (12-23 months).Major adverse cardiac events including death,non-fatal infarction,revascularization and stroke (MACE) were recorded.A Kaplan-Meier log-rank test was used to compare MACE-free survival for individuals with various genotypes.Results The frequency of-629A allele was 0.408.Compared with CC or CA genotypes,individuals with AA genotype had lower CETP levels and higher high-density lipoprotein cholesterol (HDL-C) levels,albeit without statistical significance (F-=0.893,P=0.411 and F=1.279,P=0.282,respectively).There also appeared to be a negative correlation between serum HDL-C and CETP levels,though no statistic significance was detected (r=-0.151,P=0.081).After 12 months atorvastatin therapy,individuals with CC genotype had greater reduction of low-density lipoprotein cholesterol (LDL-C),reduced LP (a) and elevated HDL-C compared with CA or AA genotypes.LDL-C level has decreased by 35.41％ in CC homozygotes,18.84 ％ in CA heterozygotes and 8.15 ％ in AA homozygotes (P=0.001).HDL-C level has increased by 14.37％ in CC homozygotes,10.48％ in CA heterozygotes and 6.64％ in AA homozygotes,respectively.However,above changes did not reach statistic significance (P=0.470).The incidence of MACE after a mean follow-up of (18.66±5.99) months was 7.76％,which included 2 (0.86％) deaths,5 (2.16％) non-fatal infarctions,9 (3.88％) revascularizations and 2 (0.86％) strokes.The cumulative MACE-free survival rates were 92.4％,85.3％ and 65.0％ for CC,CA and AA genotypes,respectively (Log-rank P=0.444).Conclusion Our results suggested that AA variant for the-629A allele of CETP gene had higher HDL-C levels and reduced CETP levels,though patients with CC genotype appeared to have better benefited from statin therapy with reduction in LDLC and LP(a) levels.Long-term clinical prognosis was however not affected by the 3 genotypes.