title: Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Taken together, our results lend support to the concept that increased HDL-C cannot be translated into a reduction in CAD risk.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wu
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Lou
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Qiu
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China. jinwei10724@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
mesh_terms: D000483:Alleles; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D016208:Databases, Factual; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D012307:Risk Factors
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL