Gao Jing, Cong Hong-liang, Mao Yong-min, Liu Yi, Zhang Nan, Chen Qian, Liu Ting, Cui Rangzhuang
Tianjin Cardiovascular Institute and Department of Cardiology, Tianjin Chest Hospital, Tianjin 300051, P. R. China. Email:
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2013 Oct;30(5):553-8. doi: 10.3760/cma.j.issn.1003-9406.2013.05.010.
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 personalized treatment.
From October 2010 to July 2011, 232 patients with angiographically confirmed CHD were recruited. Polymorphism of position -629 of 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.
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 statistical 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 statistical 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).
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 LDL-C and LP(a) levels. Long-term clinical prognosis was however not affected by the 3 genotypes.
研究天津地区汉族冠心病（CHD）患者胆固醇酯转运蛋白（CETP）基因多态性-629C/A，评估遗传因素对阿托伐他汀治疗效果及临床结局的影响，为个体化治疗提供药物基因组学依据。
2010年10月至2011年7月，招募232例经血管造影证实的CHD患者。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基因启动子-629位点的多态性。采用酶联免疫吸附测定（ELISA）法测定血清CETP水平。所有患者在基线及接受20mg/d阿托伐他汀治疗12个月后测定血脂水平。进行为期一年多（12 - 23个月）的临床随访。记录主要不良心脏事件，包括死亡、非致死性心肌梗死、血管重建和中风（MACE）。采用Kaplan-Meier对数秩检验比较不同基因型个体的无MACE生存率。
-629A等位基因频率为0.408。与CC或CA基因型相比，AA基因型个体的CETP水平较低，高密度脂蛋白胆固醇（HDL-C）水平较高，但差异无统计学意义（F = 0.893，P = 0.411和F = 1.279，P = 0.282）。血清HDL-C与CETP水平之间似乎也存在负相关，但差异无统计学意义（r = -0.151，P = 0.081）。阿托伐他汀治疗12个月后，与CA或AA基因型相比，CC基因型个体的低密度脂蛋白胆固醇（LDL-C）降低幅度更大，LP(a)降低，HDL-C升高。CC纯合子的LDL-C水平下降了35.41%，CA杂合子下降了18.84%，AA纯合子下降了8.15%（P = 0.001）。CC纯合子的HDL-C水平分别升高了14.37%，CA杂合子升高了10.48%，AA纯合子升高了6.64%。然而，上述变化差异无统计学意义（P = 0.470）。平均随访（18.66 ± 5.99）个月后，MACE发生率为7.76%，其中包括2例（0.86%）死亡、5例（2.16%）非致死性心肌梗死、9例（3.88%）血管重建和2例（0.86%）中风。CC、CA和AA基因型的累积无MACE生存率分别为92.4%、8
