Wu Zhijun, Lou Yuqing, Qiu Xiaochun, Liu Yan, Lu Lin, Chen Qiujing, Jin Wei
Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
BMC Med Genet. 2014 Oct 23;15:118. doi: 10.1186/s12881-014-0118-1.
Recent randomized controlled trials have challenged the concept that increased high density lipoprotein cholesterol (HDL-C) levels are associated with coronary artery disease (CAD) risk reduction. The causal role of HDL-C in the development of atherosclerosis remains unclear. To increase precision and to minimize residual confounding, we exploited the cholesteryl ester transfer protein (CETP)-TaqIB polymorphism as an instrument based on Mendelian randomization.
The Mendelian randomization analysis was performed by two steps. First, we conducted a meta-analysis of 47 studies, including 23,928 cases and 27,068 controls, to quantify the relationship between the TaqIB polymorphism and the CAD risk. Next, the association between the TaqIB polymorphism and HDL-C was assessed among 5,929 Caucasians. We further employed Mendelian randomization to evaluate the causal effect of HDL-C on CAD based on the findings from the meta-analysis.
The overall comparison of the B2 allele with the B1 allele yielded a significant risk reduction of CAD (P < 0.0001; OR = 0.88; 95% CI: 0.84-0.92) with substantial between-study heterogeneity (I² = 55.2%; P(heterogeneity) <0.0001). The result was not materially changed after excluding the Hardy-Weinberg Equilibrium (HWE)-violation studies. Compared with B1B1 homozygotes, Caucasian carriers of the B2 allele had a 0.25 mmol/L increase in HDL-C level (95% CI: 0.20-0.31; P <0.0001; I² = 0; P(heterogeneity) =0.87). However, a 1 standard deviation (SD) elevation in HDL-C levels due to the TaqIB polymorphism, was marginal associated with CAD risk (OR =0.79; 95% CI: 0.54-1.03; P =0.08).
Taken together, our results lend support to the concept that increased HDL-C cannot be translated into a reduction in CAD risk.
近期的随机对照试验对高密度脂蛋白胆固醇（HDL-C）水平升高与降低冠状动脉疾病（CAD）风险相关这一概念提出了挑战。HDL-C在动脉粥样硬化发展中的因果作用仍不清楚。为提高准确性并尽量减少残余混杂因素，我们利用胆固醇酯转运蛋白（CETP）-TaqIB多态性作为基于孟德尔随机化的一种手段。
孟德尔随机化分析分两步进行。首先，我们对47项研究（包括23928例病例和27068例对照）进行荟萃分析，以量化TaqIB多态性与CAD风险之间的关系。接下来，在5929名白种人中评估TaqIB多态性与HDL-C之间的关联。我们进一步基于荟萃分析的结果采用孟德尔随机化来评估HDL-C对CAD的因果效应。
B2等位基因与B1等位基因的总体比较显示CAD风险显著降低（P <0.0001；OR =0.88；95%CI：0.84 - 0.92），研究间存在显著异质性（I² =55.2%；P(异质性)<0.0001）。排除违反哈迪-温伯格平衡（HWE）的研究后，结果没有实质性变化。与B1B1纯合子相比，携带B2等位基因的白种人HDL-C水平升高0.25 mmol/L（95%CI：0.20 - 0.31；P <0.0001；I² =0；P(异质性)=0.87）。然而，由于TaqIB多态性导致的HDL-C水平升高1个标准差（SD）与CAD风险边缘相关（OR =0.79；95%CI：0.54 - 1.03；P =0.08）。
总体而言，我们的结果支持HDL-C升高不能转化为CAD风险降低这一概念。
