摘要目的 分析天津地区汉族冠心病患者胆固醇酯转运蛋白(CETP)-629C/A基因多态性,从药物基因组学角度探讨遗传因素对阿托伐他汀钙调脂疗效及患者长期临床预后的影响,为临床个体化治疗提供理论依据.方法 研究对象来自2010年10月至2011年7月天津市胸科医院心内科住院经冠状动脉造影检查证实的冠心病患者共332例,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测CETP-629C/A基因型,ELISA方法测定血清CETP含量.所有患者接受阿托伐他汀钙20 mg调脂治疗1年后复查血脂,随访12～ 23个月,记录主要不良心血管事件(MACE)[包括死亡、非致死性心肌梗死(MI)、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生存率的影响.结果 (1)A突变基因频率为0.476,C等位基因频率为0.524;CC、CA、AA基因型比较,血清高密度脂蛋白胆固醇(HDL-C)水平呈升高趋势,血清CETP水平呈降低趋势,差异均无统计学意义(分别F=0.893,P=0.411和F=1.279,P=0.282)；血清HDL-C水平与CETP浓度呈负向变化趋势,其相关性差异无统计学意义(r=-0.151,P=0.081).(2)阿托伐他汀钙20 mg调脂治疗1年后,CC基因型携带者低密度脂蛋白胆固醇(LDL-C)水平下降最多为43.5％,CA基因型次之为25.5％,AA基因型下降最少为11.7％,差异有统计学意义(P=0.001)；血清脂蛋白a[LP(a)]水平变化在不同基因型3组间差异有统计学意义(P =0.004),CC基因型下降最明显为44.2％；3种基因型患者HDL-C水平的变化虽然表现出梯度变化趋势,但差异无统计学意义(P=0.412),CC基因型HDL-C水平升高最明显为9.2％,CA基因型为6.8％,AA基因型为5.5％；对胆固醇、甘油三酯、极低密度脂蛋白胆固醇、载脂蛋白AI、载脂蛋白B的调节效果没有受到CETP多态性的影响.(3)随访(18.7±6.0)个月,发生MACE 26例(7.83％),其中死亡3例(0.90％),MI7例(2.11％),再次血运重建13例(3.92％),卒中3例(0.90％).3种基因型无MACE生存率分别为CC型96.2％,CA型92.1％,AA型87.3％,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CETP浓度,但-629CC基因型携带者有更好的他汀类调脂效果,LDL-C和LP(a)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 explore the polymorphism of cholesteryl ester transfer protein (CETP) gene-629C/A among the coronary heart disease (CHD) Han population of Tianjin area and evaluate the influences of genetic factors on atorvastatin therapeutic effects and clinical outcomes in pharmacogenomics and provide theoretical rationales for individualized treatment.Methods A total of 332 angiographically confirmed CHD patients at Tianjin Chest Hospital were recruited from October 2010 to July 2011.The CETP gene promoter polymorphism at position-629 was determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP).The serum level of CETP was determined by enzyme-linked immunosorbent assay (ELISA).Lipid levels were determined at baseline and 12 months post-treatment with 20 mg/d atorvastatin in all patients.Clinical follow-up were performed for more than 1 year (range,12-23 months).And major adverse cardiac events (MACE,including death,non-fatal infarction,revascularization and stroke) were analyzed.The Kaplan-Meier Log-rank test was used to compare MACE-free survival between different genotypes.Results (1) The frequencies of variant-692A allele was 0.476,AA genotype showed reduced CETP levels and higher HDL-C levels compared with CC and CA genotypes.But it did not reach statistical significance (F =0.893,P =0.411 and F =1.279,P =0.282 respectively).Although a negative trend correlation existed between serum levels of HDL-C and CETP,it did not reach statistical significance (r =-0.151,P =0.081).(2) After 12-month therapy of atorvastatin,CC genotype was shown to be associated with higher LDL-C,LP (a) reduction and HDL-C elevation in response to atorvastatin compared with CA and AA genotype.LDL-C levels decreased 43.5％ in CC homozygotes,25.5％ in CA heterozygotes and 11.7％ in AA homozygotes (P =0.001).HDL-C levels increased 9.2％ in CC homozygotes,6.8％ in CA heterozygotes and 5.5％ in AA homozygotes.However the changes of HDL-C levels in three genotypes showed no significant difference (P =0.412).(3)There was a 7.83％ incidence of MACE after a mean follow-up of (18.66 ± 5.99) months.The outcomes were death (n =3,0.90％),nonfatal infarction (n =7,2.11％),revascularization (n =13,3.92％) and stroke (n =3,0.90％).The cumulative MACE free survival rates were 96.2％,92.1％ and 87.3％ in CC,CA and AA genotypes respectively (Log-rank P =0.444).Conclusion Variant AA genotype shows a higher level of HDL-C s and a lowered level of CETP.However CC genotype offers a better benefit of statin therapy associated with lowered levels of LDL-C and LP(a).And the long-term clinical prognosis is not affected among three genotypes.