Carlquist John F, Muhlestein Joseph B, Horne Benjamin D, Hart Noal I, Bair Tami L, Molhuizen Henri O F, Anderson Jeffrey L
Cardiovascular Department, LDS Hospital, Salt Lake City, Utah 84143, USA.
Am Heart J. 2003 Dec;146(6):1007-14. doi: 10.1016/S0002-8703(03)00501-5.
Cholesteryl ester transfer protein (CETP) regulates plasma lipid distribution. A polymorphism in the CETP gene (Taq1B) is associated with CETP activity, HDL concentration, atherosclerosis progression, and response to statins, and may influence cardiovascular (CV) events. We studied CETP Taq1B genotype, plasma HDL, and clinical events among all patients and patients stratified by statin treatment.
Consenting patients (n = 2531) with significant coronary artery disease (> or =1 lesion of > or =70% stenosis) undergoing coronary arteriography were genotyped, grouped by statin prescription at hospital discharge, and prospectively followed-up for the outcomes of all-cause mortality and myocardial infarction.
CETP Taq1B genotype frequencies were: B1B1, 32.9%; B1B2, 50.3%; and B2B2 16.8%. Plasma HDL was reduced for B1B1 patients (33 +/- 12 mg/dL, vs 36 +/- 13 mg/dL and 36 +/- 13 mg/dL for B1B2 and B2B2, respectively, P for trend =.003). Overall, event rates did not differ between genotypes. Event rates were similar among untreated (24.8%) and statin-treated (24.2%) B1 homozygotes (P = NS); statins significantly reduced events for B1B2 subjects (28.0% vs 21.0%, P =.009) and for B2B2 subjects (26.4% vs 17.4%, P =.048). Therapeutic benefit for B2 carriers remained after adjustment for covariates, and regression interaction analysis showed that B2 carriers experienced reduced events (relative risk [RR] 0.62, 95% CI 0.45-0.86), but statins did not benefit those with B1B1 (RR 1.09, 95% CI 0.70-1.7; P for interaction =.02). Findings were similar for the end point of death alone, although a modest benefit was seen in B1B1 patients (RR 0.67, P =.10), in addition to the strong benefit for B1B2 (RR 0.53, P =.001) and B2B2 (RR 0.28, P =.001).
The CETP Taq1B polymorphism is associated with differential HDL levels but no significant differential in CV risk in the absence of treatment. Importantly, however, CV event reduction by statin therapy is substantially enhanced in the presence of a B2 allele. Our findings suggest, for the first time, the potential of CETP Taq1B genotyping to enable more effective, pharmacogenetically directed therapy.
胆固醇酯转运蛋白（CETP）调节血浆脂质分布。CETP基因中的一种多态性（Taq1B）与CETP活性、高密度脂蛋白（HDL）浓度、动脉粥样硬化进展以及对他汀类药物的反应相关，并且可能影响心血管（CV）事件。我们研究了所有患者以及根据他汀类药物治疗分层的患者中的CETP Taq1B基因型、血浆HDL和临床事件。
对2531例接受冠状动脉造影且患有严重冠状动脉疾病（≥1处病变，狭窄≥70%）并同意参与研究的患者进行基因分型，根据出院时的他汀类药物处方分组，并对全因死亡率和心肌梗死的结局进行前瞻性随访。
CETP Taq1B基因型频率分别为：B1B1，32.9%；B1B2，50.3%；B2B2，16.8%。B1B1患者的血浆HDL降低（分别为33±12mg/dL，而B1B2和B2B2分别为36±13mg/dL和36±13mg/dL，趋势P = 0.003）。总体而言，各基因型之间的事件发生率没有差异。未治疗的（24.8%）和他汀类药物治疗的（24.2%）B1纯合子之间的事件发生率相似（P = 无显著性差异）；他汀类药物显著降低了B1B2受试者（28.0%对21.0%，P = 0.009）和B2B2受试者（26.4%对17.4%，P = 0.048）的事件发生率。在对协变量进行调整后，B2携带者的治疗益处仍然存在，回归交互分析表明B2携带者经历的事件减少（相对风险[RR] 0.62，95%可信区间0.45 - 0.86），但他汀类药物对B1B1患者没有益处（RR 1.09，95%可信区间0.70 - 1.7；交互作用P = 0.02）。仅对于死亡终点，结果相似，尽管在B1B1患者中观察到适度益处（RR 0.67，P = 0.10），此外B1B2（RR 0.53，P = 0.001）和B2B2（RR 0.28，P = 0.001）有显著益处。
CETP Taq1B多态性与HDL水平差异相关，但在未治疗时CV风险无显著差异。然而，重要的是，在存在B2等位基因的情况下，他汀类药物治疗可显著降低CV事件。我们的研究结果首次表明，CETP Taq1B基因分型具有实现更有效、基于药物遗传学指导治疗的潜力。
