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. 2016 Sep 5;13(9):882. doi: 10.3390/ijerph13090882

Associations of Cholesteryl Ester Transfer Protein TaqIB Polymorphism with the Composite Ischemic Cardiovascular Disease Risk and HDL-C Concentrations: A Meta-Analysis

Shu-xia Guo 1,2,†, Ming-hong Yao 1,2,†, Yu-song Ding 1,2, Jing-yu Zhang 1,2, Yi-zhong Yan 1,2, Jia-ming Liu 1,2, Mei Zhang 1,2, Dong-sheng Rui 1,2, Qiang Niu 1,2, Jia He 1,2, Heng Guo 1,2, Ru-lin Ma 1,2,*
Editor: William Chi-shing Cho
PMCID: PMC5036715  PMID: 27608031

Abstract

Background: Previous studies have evaluated the associations between the cholesteryl ester transfer protein (CETP) TaqIB polymorphism (rs708272), the risk of developing composite ischemic cardiovascular disease (CVD) and the concentration of high-density lipoprotein cholesterol (HDL-C), but results remain controversial. The objective of this study was to investigate whether a relationship exists between these factors. Methods: We conducted a meta-analysis of available studies to clarify the associations of the CETP TaqIB polymorphism with HDL-C concentration and the composite ischemic CVD risk in both Asians and Caucasians. All statistical analyses were done with Stata 12.0. Results: Through utilization of the Cochrane Library, Embase, PubMed, Web of Science, Springer, China Science and Technology Journal Database, China National Knowledge Infrastructure, Google Scholar, and Baidu Library, a total of 45 studies from 44 papers with 20,866 cases and 21,298 controls were combined showing a significant association between the CETP TaqIB variant and composite ischemic CVD risk. Carriers of allele TaqIB-B1 were found to have a higher risk of composite ischemic CVD than non-carriers: OR = 1.15, 95% CI = 1.09–1.21, p < 0.001. Meanwhile, 28 studies with 23,959 subjects were included in the association between the CETP TaqIB polymorphism and the concentration of HDL-C. Results suggested that carriers of the B1B1 genotype had lower concentrations of HDL-C than those of the B2B2 genotype: SMD = 0.50, 95% CI = 0.36–0.65, p < 0.001. Conclusions: The synthesis of available evidence demonstrates that the CETP TaqIB polymorphism protects against composite ischemic CVD risk and is associated with a higher HDL-C concentration in both Asians and Caucasians.

Keywords: cholesteryl ester transfer protein, polymorphism, composite ischemic cardiovascular disease, HDL-C, meta-analysis

1. Introduction

Composite ischemic cardiovascular disease (CVD), including coronary artery disease (CAD), ischemic stroke (IS), and myocardial infarction (MI) has become a serious public health problem around the world because of their high morbidity and mortality [1,2]. However, their exact mechanisms are still unclear. For a long time, atherosclerosis (AS) has attracted attention because it is the pathological foundation of CAD, IS, and MI. Abnormal cholesterol metabolism was considered to be the main factor for atherosclerosis, and epidemiological evidence considered low concentrations of serum high-density lipoprotein cholesterol (HDL-C) to be an independent risk factor [3,4]. However, high-density lipoprotein (HDL) has now been shown to play a pivotal role in mediating the transfer of cholesterol from extra hepatic tissues to the liver and reducing the deposition of cholesterol on the artery wall [5].

Serum HDL-C concentrations are affected by many genetic and environmental factors. The cholesteryl ester transfer protein (CETP) gene located on chromosome 16q21, encodes the key plasma protein that mediates the transfer of esterified cholesterol from HDL to apolipoprotein B-containing particles in exchange for triglycerides [6,7]. Mutation of the gene may affect the transcription and expression of CETP, thereby affecting serum HDL-C concentrations [8]. The CETP TaqIB (rs708272) polymorphism is the most common polymorphism in intron 1 of the CETP gene and its mutation can affect the concentration as well as activity of plasma CETP, which affected the level of HDL-C [9]. Recently, though numerous studies have shown a relationship between the CETP TaqIB polymorphism in the synthesis of HDL-C and composite ischemic CVD risk, research has remained inconsistent, possibly due to the small sample sizes used in the individual studies.

In 2005, Boekholdt et al. performed a meta-analysis to evaluate the association the CETP TaqIB polymorphism in the synthesis of serum HDL-C and CAD risk, and demonstrated that the CETP TaqIB variant is associated with HDL-C level and CAD risk in Caucasians [10]. Li et al. also conducted a meta-analysis to evaluate the association of this variant with CAD in Chinese; however, no relationship between the CETP TaqIB polymorphism and CAD was observed [11]. Cao et al. and Wang et al. performed meta-analysis to evaluate the association the CETP TaqIB variant and MI. Their results showed that the CETP TaqIB-B2 allele protects against the development of MI [12,13]. No meta-analysis was found on the association between the CETP TaqIB polymorphism and IS. Considering the four meta-analyses above focused only on the association of the CETP TaqIB polymorphism with a single atherosclerotic disease and results were controversial in regards to ethnicity (Asians and Caucasians), we performed this meta-analysis to clarify the role of the CETP TaqIB polymorphism in the synthesis of HDL-C and the composite ischemic CVD risk.

2. Materials and Methods

2.1. Literature Search

The protocol was approved by the Institutional Ethics Review Board (IERB) of the First Affiliated Hospital of Shihezi University School of Medicine (IERB No. SHZ2010LL01). Using the standards of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE) [14] and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [15], searches were performed using the following electronic databases: the Cochrane Library, Embase, PubMed, Web of Science, Springer, China Science and Technology Journal Database (CSTJ), China National Knowledge Infrastructure (CNKI), Google Scholar, and Baidu Library (the last search was conducted on 31 January 2016). Searches were performed using combinations of the following key words: (“cholesteryl ester transfer protein” OR “CETP”) and (“variation” OR “variant” OR “mutation” OR “polymorphism” OR “genotype”) and (“CAD” OR “coronary artery disease” OR “coronary heart disease” OR “CHD” OR “myocardial infarction” OR “MI” OR “ischemic cardiovascular disease” OR “IS”) and (“high-density lipoprotein cholesterol” OR “HDL-C” OR “blood lipid” OR “serum lipid”).

2.2. Eligibility Criteria

The eligibility criteria for the inclusion of articles in the present meta-analysis were the following: (1) The publication evaluated the associations of the CETP TaqIB polymorphism with AS or HDL-C level; (2) CAD and MI diagnosis required the result of coronary angiography, and the diagnosis of IS depended on the result of magnetic resonance imaging or computed tomography; (3) published in either Chinese or English; (4) for the composite ischemic CVD association, sufficient published data for calculating odds ratios (ORs) with their 95% confidence intervals (CIs); for HDL-C concentrations association, the population, the mean of HDL-C concentrations, and the standard deviations (SD) by genotype should be available.

2.3. Exclusion Criteria

The exclusion criteria were as follows: (1) Duplicate publications; (2) incomplete information; (3) insufficient or insignificant statistical data; (4) review articles.

2.4. Data Extraction

Two reviewers (Minghong Yao and Yusong Ding) independently screened full-length articles according to the pre-specified inclusion criteria. For the composite ischemic CVD association, the following information was extracted: name of the first author, year of publication, study population (country, ethnicity), source of controls, case/control sample size, minor allele frequency (MAF), genotype counts in the cases/controls, and evidence of Hardy-Weinberg equilibrium (HWE); for HDL-C concentrations association, name of the first author, year of publication, study population (country, ethnicity), population number, mean of HDL-C concentrations, and their SD by genotype. If key data were not presented in the relevant publications, we tried to obtain them directly from the authors of the relevant studies. When the two reviewers’ opinions differed, a third reviewer (ShuXia Guo) was asked to make final decisions regarding the results.

2.5. Quality Assessment for Individual Studies

The Newcastle-Ottawa Scale (NOS) was used to assessed the methodologic quality of the individual studies by two reviewers (Minghong Yao and Yizhong Yan) [16]. Each study was evaluated and scored based on three criteria: selection (4 stars), comparability (2 stars), and exposure (3 stars). The NOS point ranges between zero up to nine stars. Any disagreement was resolved by discussion with a third reviewer (Jiaming Liu).

2.6. Data Analysis

All statistics were analyzed in Stata 12.0 (StataCorp, College Station, TX, USA). All the tests were two-sided and a p-value of less than 0.05 was considered statistically significant. The HWE was assessed using the chi-square test. The strength of associations between the CETP TaqIB polymorphism and atherosclerosis were assessed by summary odds ratios (ORs) with 95% confidence intervals (CIs). Pooled ORs were performed for the allele contrasts as followed: (B1 allele vs. B2 allele), additive genetic model (B1B1 vs. B2B2), recessive genetic model (B1B1 vs. B1B2 + B2B2), and dominant genetic model (B1B1 + B1B2 vs. B2B2), respectively. A pooled standardized mean difference (SMDs) and its 95% CIs were used for the meta-analysis of HDL-C concentrations and the CETP TaqIB polymorphism. Heterogeneity across individual studies was calculated using the Cochran’s-Q statistic and the I2 statistic (p < 0.10 and I2 > 50% indicated evidence of heterogeneity) [17,18]. With no heterogeneity among studies, the ORs or SMDs estimate of each study was calculated by the fixed effect model (Mantel-Haenszel) [19]. Otherwise, the random effect model (DerSimonian and Laird) was used [20,21]. Subsequently, the Galbraith plot and meta-regression were performed to explore the sources of heterogeneity [22]. For the composite ischemic CVD association, subgroup analyses were performed based on ethnicity, atherosclerotic diseases, source of controls, and study type; for HDL-C association, subgroup analyses were performed based on ethnicity. Sensitivity analyses were performed based on HWE (studies without HWE were excluded) and sample size (n < 400 were excluded). Potential risk of publication bias was tested by funnel plot and Egger’s test.

3. Results

3.1. Selection and Characteristics of Studies

The present study met the PRISMA statements (Checklist S1) and MOOSE guidelines (Table S1). The study selection process is detailed in Figure 1. Through a comprehensive retrieval and evaluation, 45 studies from 44 papers with 20,866 cases and 21,298 controls met the inclusion criteria to assess the association between the CETP TaqIB polymorphism and the composite ischemic CVD [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65]. The selected study characteristics and data are listed in Table 1. Among these studies, 28 involved CAD [23,24,25,26,27,28,29,30,31,32,34,35,36,37,38,39,44,46,47,50,52,53,54,55,59,60,61,66], three involved IS [63,64,65], and 14 involved MI [33,40,41,42,43,45,48,49,51,56,57,58,62]. In addition, there were 26 studies on Caucasians [23,24,25,27,30,38,39,40,41,42,43,44,45,47,48,50,51,53,56,57,58,60,62,63,64] and 19 studies on Asians [26,28,29,31,32,33,34,35,36,37,46,49,52,54,55,59,61,65,66]. Controls of 23 studies were hospital-based [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,57,58,59,61,63,64,65,66], while those of the other 22 studies were population-based [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,60,62]. Seven studies did not follow the Hardy-Weinberg equilibrium [23,35,36,40,42,43,58]. In addition, NOS results showed that the average scores were 6.8.

Figure 1.

Figure 1

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Flow diagram of the study selection process.

Table 1.

Characteristics of individual studies included in the meta-analysis of atherosclerosis and the CETP TaqIB polymorphism.

First Author Year Country Ethnicity Disease Source of Controls Study Type Size (Case/Control) MAF HWE Genotypes Distribution (Case/Control) Score
B1B1 B1B2 B2B2
Tenkanen et al. [51] 1991 Finland Caucasian MI PB CS 72/115 0.44 Yes 19/33 40/65 13/17 8
Fumeron et al. [41] 1995 France Caucasian MI PB CCS 608/724 0.40 Yes 209/258 312/346 87/120 8
Kuivenhoven et al. [44] 1998 The Netherlands Caucasian CAD PB CS 380/427 0.41 Yes 129/152 183/214 68/61 7
Wu et al. [33] 2001 China Asian MI HB CCS 149/274 0.46 Yes 45/63 79/159 25/52 8
Arca et al. [38] 2001 Italy Caucasian CAD PB CCS 408/180 0.41 Yes 153/67 187/77 68/36 8
Eiriksdottir et al. [40] 2001 Iceland Caucasian MI PB CS 378/745 0.45 No 128/194 191/396 59/155 8
Liu et al. [45] 2002 USA Caucasian MI PB CS 384/384 0.43 Yes 125/122 196/193 63/69 8
Freeman et al. [56] 2003 UK Caucasian MI PB CS 499/1105 0.50 Yes 164/239 259/541 76/225 8
Zhang et al. [35] 2003 China Asian CAD HB CCS 234/164 0.41 No 76/49 126/95 32/20 6
Qin et al. [29] 2004 China Asian CAD HB CCS 249/167 0.41 Yes 81/49 131/97 37/21 6
Wang et al. [32] 2004 China Asian CAD HB CCS 128/247 0.42 Yes 50/72 66/123 12/52 6
Yan et al. [34] 2004 China Asian CAD HB CCS 106/64 0.41 Yes 41/19 46/34 19/11 6
Zhao et al. [36] 2004 China Asian CAD HB CCS 238/203 0.41 No 95/60 105/109 38/34 6
Zheng et al. [37] 2004 China Asian CAD HB CCS 203/100 0.39 Yes 66/33 114/55 23/12 6
Bernard et al. [43] 2004 UK Caucasian MI PB CCS 4442/3273 0.43 No 1477/1100 2175/1527 790/646 8
Yilmaz et al. [42] 2005 Turkey Caucasian MI PB CCS 173/111 0.42 No 66/39 72/46 35/26 6
Fidani et al. [63] 2005 Greek Caucasian IS HB CCS 96/100 0.41 Yes 35/34 47/45 14/21 6
Whiting et al. [53] 2005 USA Caucasian CAD PB CS 2392/827 0.42 Yes 792/279 1200/377 400/171 8
Zhang et al. [54] 2005 China Asian CAD PB CCS 88/94 0.41 Yes 31/32 40/50 17/12 6
Dedoussis et al. [57] 2007 Greece Caucasian MI HB CCS 237/237 0.41 Yes 83/78 121/120 33/39 7
Morgan et al. [58] 2007 USA Caucasian MI HB CCS 805/656 0.44 No 250/224 387/297 168/135 6
Hsieh et al. [59] 2007 China Asian CAD HB CCS 101/264 0.31 Yes 19/23 47/111 35/130 5
Quarta et al. [64] 2007 Italy Caucasian IS HB CCS 215/236 0.43 Yes 79/73 105/108 31/55 6
Muendlein et al. [27] 2008 Austria Caucasian CAD HB CS 332/225 0.40 Yes 125/71 162/116 45/38 8
Rejeb et al. [30] 2008 Tunisian Caucasian CAD HB CS 212/104 0.41 Yes 104/45 93/47 15/12 8
Meiner et al. [48] 2008 USA Caucasian MI PB CCS 550/620 0.45 Yes 173/166 282/320 95/134 6
Wang et al. [52] 2008 China Asian CAD PB CCS 317/298 0.41 Yes 117/99 148/146 52/53 6
Jensen et al. [62] a 2008 USA Caucasian MI PB CS 247/486 0.42 Yes 84/166 120/235 42/85 8
Jensen et al. [62] b 2008 USA Caucasian MI PB CS 259/513 0.41 Yes 89/180 126/244 44/89 8
Padmaja et al. [28] 2009 Indian Asian CAD HB CCS 504/338 0.45 Yes 163/86 264/161 77/91 6
Poduri et al. [49] 2009 India Asian MI PB CCS 265/150 0.41 Yes 117/3 107/82 41/35 6
Tanrikulu-Kucuk et al. [23] 2010 Turkey Caucasian CAD HB CCS 135/112 0.46 No 40/33 71/50 24/29 6
Corella et al. [39] 2010 Spanish Caucasian CAD PB CS 557/1180 0.47 Yes 224/482 247/537 86/161 8
Bhanushali et al. [66] 2010 Indian Asian CAD HB CCS 90/150 0.46 Yes 33/38 40/77 17/35 7
Kolovou et al. [25] 2011 Greek Caucasian CAD HB CCS 374/96 0.42 Yes 126/22 202/45 46/29 6
Zhang et al. [55] 2011 China Asian CAD PB CCS 334/301 0.34 Yes 172/136 106/120 56/45 8
Jiang et al. [65] 2012 China Asian IS HB CCS 220/220 0.29 Yes 130/103 72/86 18/31 6
Tayebi et al. [61] 2012 Singapore Asian CAD HB CCS 659/927 0.45 Yes 228/245 322/491 109/191 7
Lu et al. [46] 2013 Singapore Asian CAD PB CCS 659/927 0.45 Yes 228/245 322/491 109/191 8
Mehlig et al. [47] 2014 Sweden Caucasian CAD PB CCS 618/2921 0.43 Yes 209/938 313/1420 96/563 8
El-Aziz et al. [50] 2014 Egypt Caucasian CAD PB CCS 116/119 0.46 Yes 38/30 60/57 18/32 6
Kaman et al. [24] 2015 Turkey Caucasian CAD HB CCS 210/100 0.44 Yes 44/29 81/45 85/26 6
Liu et al. [26] 2015 China Asian CAD HB CCS 322/108 0.42 Yes 113/40 145/47 64/21 6
Shi et al. [31] 2015 China Asian CAD HB CCS 312/88 0.42 Yes 112/29 138/44 62/15 6
Cyrus et al. [60] 2016 Saudi Arabia Caucasian CAD PB CCS 990/618 0.41 Yes 376/183 454/321 160/114 6
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a: Nurses’ Health Study, b: Health Professionals Follow-up Study, USA: The United States, UK: United Kingdom, CAD: coronary artery disease, MI: myocardial infraction, IS: ischemic stroke, HB: hospital-based, PB: population-based, MAF: minor allele frequencies, HWE: Hardy-Weinberg equilibrium, CS: cohort study, CCS: case control study.

Table 2 describes the characteristics of studies included in the association between the CETP TaqIB polymorphism and serum HDL-C concentrations. A total of 28 studies with 23,959 subjects were included in the analysis [8,33,35,36,40,44,45,50,53,59,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85]. Of these, there were 11 studies on Caucasians [8,40,44,45,50,53,67,69,71,81,83] and 17 studies on Asians [33,35,36,59,68,70,72,73,74,75,76,77,78,79,80,82,84,85]. Five studies did not follow the HWE [35,72,74,76,77]. Additionally, NOS results showed that the average scores were 6.4.

Table 2.

Characteristics of individual studies included in the meta-analysis of HDL-C level and the CETP TaqIB polymorphism.

First Author Year Country Ethnicity MAF HWE B1B1 B1B2 B2B2 Score
Mean SD n Mean SD n Mean SD n
Kuivenhoven et al. [44] 1998 The Netherlands Caucasian 0.41 Yes 0.88 0.21 281 0.93 0.21 397 1.01 0.26 129 7
Gudnason et al. [67] 1999 Mixed Caucasian 0.44 Yes 1.13 0.21 237 1.19 0.24 380 1.27 0.22 150 7
Eiriksdottir et al. [40] 2001 Iceland Caucasian 0.45 Yes 1.09 0.31 328 1.12 0.29 596 1.25 0.40 210 8
Goto et al. [68] 2001 Japan Asian 0.43 Yes 1.14 0.28 37 1.23 0.37 47 1.23 0.33 22 6
Talmud et al. [8] 2002 UK Caucasian 0.45 Yes 0.79 0.25 500 0.84 0.25 896 0.90 0.27 317 6
Liu et al. [45] 2002 USA Caucasian 0.43 Yes 1.17 0.28 247 1.24 0.34 389 1.30 0.34 132 8
Goff et al. [69] 2002 UK and France Caucasian 0.47 Yes 1.33 0.40 410 1.29 0.60 889 1.26 0.45 504 7
Zhang et al. [35] 2003 China Asian 0.41 No 1.26 0.22 125 1.30 0.25 221 1.42 0.22 52 6
Katsunori et al. [70] 2003 Japan Asian 0.4 Yes 1.32 0.46 217 1.43 0.57 279 1.59 0.62 95 7
Zhao et al. [36] 2004 China Asian 0.41 Yes 1.19 0.36 155 1.27 0.34 214 1.38 0.39 72 6
Weitgasser et al. [71] 2004 Austrian Caucasian 0.41 Yes 1.49 0.39 358 1.55 0.41 475 1.67 0.41 184 7
Jiang et al. [72] 2005 China Asian 0.37 No 1.16 0.27 49 1.20 0.33 38 1.34 0.29 21 6
Whiting et al. [53] 2005 USA Caucasian 0.42 Yes 0.91 0.33 1071 0.95 0.34 1577 1.00 0.38 571 8
Huang et al. [73] 2006 China Asian 0.40 Yes 1.08 0.29 121 1.13 0.29 163 1.27 0.48 56 6
Zhang et al. [74] 2007 China Asian 0.40 No 1.26 0.31 24 1.34 0.35 20 1.42 0.43 13 6
Cui et al. [75] 2007 China Asian 0.46 Yes 1.44 0.32 17 1.58 0.46 24 1.54 0.36 13 6
Meena et al. [76] 2007 Indian Asian 0.21 No 1.20 0.20 15 1.10 0.10 36 1.10 0.20 106 6
Hsieh et al. [59] 2007 China Asian 0.31 Yes 43.31 10.63 42 43.39 11.09 158 46.24 11.83 165 5
Zhang et al. [77] 2008 China Asian 0.39 No 1.45 0.31 46 1.41 0.23 78 2.03 0.47 16 6
Wang et al. [78] 2008 China Asian 0.44 Yes 1.31 0.38 66 1.39 0.38 98 1.61 0.44 41 6
Qiu et al. [79] 2009 China Asian 0.41 Yes 1.18 0.36 38 1.25 0.33 32 1.28 0.42 21 6
Tao et al. [80] 2010 China Asian 0.41 Yes 0.95 0.19 608 0.96 0.18 939 0.97 0.18 272 6
Kappelle et al. [81] 2013 The Netherlands Caucasian 0.42 Yes 1.28 0.37 2301 1.35 0.40 3233 1.41 0.42 1246 6
Li et al. [82] 2014 China Asian 0.33 Yes 0.99 0.23 82 1.10 0.32 73 1.10 0.27 21 6
Galati et al. [83] 2014 Italia Caucasian 0.42 Yes 1.52 0.45 73 1.45 0.30 106 1.61 0.42 39 7
El-Aziz et al. [50] 2014 Egypt Caucasian 0.49 Yes 0.81 0.11 68 1.14 0.21 117 1.53 0.19 62 6
Zhai et al. [84] 2015 China Asian 0.48 Yes 0.96 0.28 12 1.10 0.25 34 1.12 0.31 14 6
Jeenduang et al. [85] 2015 Thailand Asian 0.37 Yes 1.34 0.32 152 1.35 0.35 169 1.39 0.31 57 6
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USA: The United States, UK: United Kingdom, HWE: Hardy-Weinberg equilibrium, SD: standard deviation, HDL-C: High density lipoprotein cholesterol, MAF: minor allele frequencies.

3.2. Association between the CETP TaqIB Polymorphism and the Composite Ischemic CVD Risk

The results of all 45 comparisons showed evidence of a significant association between the CETP TaqIB polymorphism and the composite ischemic CVD, suggesting that carriers of allele TaqIB-B1 have a higher risk of the composite ischemic CVD than non-carriers (OR = 1.15, 95% CI = 1.09–1.21) (Figure 2). The additive genetic model (B1B1 vs. B2B2: OR = 1.26, 95% CI = 1.19–1.34), dominant genetic model (B1B1 + B1B2 vs. B2B2: OR = 1.20, 95% CI = 1.14–1.27), and recessive genetic model (B1B1 vs. B1B2 + B2B2: OR = 1.13, 95% CI = 1.08–1.18) were also included in the analysis and results were similar with allele comparison (Figures S1–S3). Subgroup analyses by ethnicity showed significant associations in Asians consistent with that in Caucasians. In addition, significant associations were also found between this variant and susceptibility to the composite ischemic CVD in the population-based group, the hospital-based group, the CAD group, the MI group, the IS group, the case control study group, and the cohort study group, respectively. We also observed the association between CETP TaqIB-B2 polymorphism and the composite ischemic CVD risk where was stronger in the Asian than the Caucasians. The main results of the meta-analysis are shown in Table 3.

Figure 2.

Figure 2

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Meta-analysis of atherosclerosis and the CETP TaqIB polymorphism (B1 vs. B2).

Table 3.

Metal-analysis of CETP TaqIB polymorphism and risk of atherosclerosis in each subgroup.

Position Size (Case/Control) Allele Model Additive Model Recessive Model Dominant Model
OR (95% CI) p Value OR (95% CI) p Value OR (95% CI) p Value OR (95% CI) p Value
Overall analysis 20,866/21,298 1.15 (1.09–1.21) p < 0.001 1.26 (1.19–1.34) p < 0.001 1.13 (1.08–1.18) p < 0.001 1.20 (1.14–1.27) p < 0.001
Subgroup analysis based on ethnicity
Asian 5178/5084 1.24 (1.15–1.35) p < 0.001 1.52 (1.35–1.72) p < 0.001 1.41 (1.29–1.53) p < 0.001 1.28 (1.15–1.42) p < 0.001
Caucasian 15,688/16,214 1.09 (1.04–1.16) 0.001 1.19 (1.11–1.27) p < 0.001 1.05 (1.00–1.11) 0.041 1.18 (1.11–1.25) p < 0.001
Subgroup analysis based on type of diseases
MI 9067/9393 1.10 (1.03–1.19) 0.009 1.18 (1.08–1.29) p < 0.001 1.05 (0.99–1.12) 0.104 1.17 (1.08–1.26) p < 0.001
IS 531/556 1.39 (1.17–1.66) p < 0.001 1.92 (1.33–2.77) 0.001 1.40 (1.09–1.79) p < 0.001 1.76 (1.25–2.47) 0.001
CAD 11,268/11,349 1.15 (1.08–1.24) p < 0.001 1.31 (1.21–1.43) p < 0.001 1.19 (1.12–1.27) p < 0.001 1.21 (1.13–1.31) p < 0.001
Subgroup analysis based on source of controls
PB 14,735/11,618 1.11 (1.05–1.17) p < 0.001 1.21 (1.13–1.29) p < 0.001 1.09 (1.04–1.15) 0.001 1.17 (1.10–1.25) p < 0.001
HB 6131/5180 1.20 (1.10–1.31) p < 0.001 1.42 (1.26–1.59) p < 0.001 1.24 (1.14–1.35) p < 0.001 1.28 (1.16–1.42) p < 0.001
Subgroup analysis based on study type
CCS 15,155/15,187 1.14 (1.10–1.18) p < 0.001 1.30 (1.21–1.39) p < 0.001 1.16 (1.11–1.22) p < 0.001 1.22 (1.15–1.30) p < 0.001
CS 5711/6111 1.07 (1.01–1.13) 0.023 1.16 (1.03–1.30) 0.012 1.05 (0.97–1.14) 0.277 1.15 (1.04–1.28) 0.007
Sensitivity analysis
BHWE 14,461/16,034 1.16 (1.09–1.23) p < 0.001 1.33 (1.23–1.42) p < 0.001 1.18 (1.12–1.24) p < 0.001 1.24 (1.16–1.32) p < 0.001
BS 18,902/19,454 1.12 (1.08–1.15) p < 0.001 1.25 (1.18–1.33) p < 0.001 1.13 (1.08–1.18) p < 0.001 1.20 (1.14–1.27) p < 0.001
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CAD: coronary artery disease, MI: myocardial infraction, IS: ischemic stroke, HB: hospital-based, PB: population-based, HWE: Hardy-Weinberg equilibrium, CS: cohort study, CCS: case control study, BHWE: based on Hardy-Weinberg equilibrium (Studies without Hardy-Weinberg equilibrium were excluded), BS: based on sample size (Studies with sample size < 400 were excluded).

3.3. Association between the CETP TaqIB Polymorphism and HDL-C Concentrations

Figure 3 describes the results of the meta-analysis of the CETP TaqIB polymorphism and HDL-C concentrations. Our analysis strongly suggested that carriers of the B1B1 genotype had lower concentrations of HDL-C than those of the B2B2 genotype (B1B1 vs. B2B2: SMD = 0.50, 95% CI = 0.36–0.65). We also compared carriers of the B1B1 genotype with those of the B1B2 genotype (Figure S4: B1B1 vs. B1B2: SMD = 0.18, 95% CI = 0.10–0.26) and B1B2 genotype with those of B2B2 genotype (Figure S5: B1B2 vs. B2B2: SMD = 0.32, 95% CI = 0.21–0.42). Subgroup analyses by ethnicity confirmed that the relationship between the CETP TaqIB-B2 polymorphism and the HDL-C concentration in Asians was less consistent than that in Caucasians (Figure 2, Figures S4 and S5).

Figure 3.

Figure 3

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Association between the CETP TaqIB polymorphism and HDL-C level (B1B1 vs. B2B2).

3.4. Sensitivity Analysis

Sensitivity analysis was performed to determine the robustness of the study results. The included studies were limited to those conforming to HWE and sample size. We performed sensitivity analysis by removing studies without HWE and an n < 400. Overall, the corresponding pooled ORs and SMD were not materially altered for either analysis. Results of the sensitivity analysis suggested that the overall results were relatively robust and credible. The main results of the sensitivity analyses are shown in Table 3 and Figures S6–S11.

3.5. Heterogeneity Analysis

For the relationship between the CETP TaqIB polymorphism and the composite ischemic CVD, significant heterogeneity among the available studies were observed in the overall comparisons for the allelic model: PQ < 0.001, I2 = 57.8%; additive model: PQ < 0.001, I2 = 55.8%; recessive model: PQ < 0.001, I2 = 52.0%; and dominant model: PQ = 0.001, I2 = 41.7%. To clarify the sources of heterogeneity, we conducted a meta-regression analysis. The results showed that heterogeneity can be explained by the source of controls for the allelic model: p = 0.046, additive model: p = 0.025, and dominant model: p = 0.039, and ethnicity for the additive model: p = 0.048.

For the relationship between the CETP TaqIB polymorphism and HDL-C concentrations, significant heterogeneity among the available studies was also observed in the overall comparisons for B1B1 vs. B2B2: PQ < 0.001, I2 = 90.8%; B1B1 vs. B1B2: PQ < 0.001, I2 = 79.9%; and B1B2 vs. B2B2: PQ < 0.001, I2 = 85.1%. Four studies were identified as the main contributors of heterogeneity in the Asian studies [74,76,77,80] and four studies were identified as the main contributors of heterogeneity in the Caucasian studies [44,50,67,69] using the Galbraith plot (Figures S12 and S13). Figures S14–S16 show the association between the CETP TaqIB polymorphism and HDL-C concentrations after exclusion of these outlier studies. However, the significant association between the CETP polymorphism and HDL-C concentrations was unchanged both in the Asian subgroup (B1B1 vs. B2B2: SMD = 0.47, 95% CI = 0.36–0.57; B1B1 vs. B1B2: SMD = 0.19, 95% CI = 0.11–0.26; B1B2 vs. B2B2: SMD = 0.28, 95% CI = 0.18–0.37) and Caucasian subgroup (B1B1 vs. B2B2: SMD = 0.35, 95% CI = 0.30–0.40; B1B1 vs. B1B2: SMD = 0.16, 95% CI = 0.12–0.19; B1B2 vs. B2B2: SMD = 0.19, 95% CI = 0.15–0.20).

3.6. Publication Bias

Funnel plots and Egger’s test were performed to access the publication bias of literature. For the CETP polymorphism and the composite ischemic CVD risk analysis (B1 vs. B2), the shape of the funnel plot (Figure 4) did not reveal obvious asymmetry, which means no publication bias. This was confirmed by Egger’s test (p = 0.074). For the CETP polymorphism and HDL-C analysis (B1B1 vs. B2B2), neither the shape of the funnel plot (Figure 5) nor Egger’s test (p = 0.058) revealed any obvious asymmetry.

Figure 4.

Figure 4

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Funnel plot for allele comparison of atherosclerosis and the CETP TaqIB polymorphism. Each small circle represents a separate study for the indicated association.

Figure 5.

Figure 5

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Funnel plot of CETP TaqIB polymorphism and HDL-C level (B1B1 vs. B2B2). Each small circle represents a separate study for the indicated association.

4. Discussion

In the present meta-analysis, a total of 45 studies from 44 papers with 20,866 cases and 21,298 controls, we found that the TaqIB-B2 allele was significantly associated with reduction of composite ischemic CVD both in Caucasians and Asians. Additionally, 28 studies with 23,959 subjects were included in the analysis on the association between the CETP TaqIB polymorphism and HDL-C concentrations. According to the results, the TaqIB-B2 allele was significantly associated with a higher level of HDL-C both in Caucasians and Asians. Therefore, it is reasonable to assume that the CETP TaqIB polymorphism is influencing HDL-C metabolism to protect against the development of AS. This result suggests that we can use CETP inhibitors to prevent and treat dyslipidemia and the composite ischemic CVD. In 2014, Keene et al. performed a meta-analysis to investigate association between the CETP inhibitors and cardiovascular outcomes [86]. The results show that CETP inhibitors neither increase the serum HDL-C concentration nor reduce the mortality rate of the composite ischemic CVD. It is probably because the trial design or the use of a drug with serious off-target adverse effects. On the other hand, it is well known that the serum HDL-C concentrations affected by multiple environmental and genetic factors. Therefore, the use of CETP inhibitor alone may not be able to reduce the risk of having a clinical atherosclerotic cardiovascular event.

To create a more comprehensive analysis of the association between the CETP TaqIB polymorphism and composite ischemic CVD, we performed subgroup analyses based on ethnicity, source of controls, atherosclerotic disease, and study type in the allelic model, additive model, recessive model, and dominant model. Significant associations were found between this variant and susceptibility to composite ischemic CVD in the Caucasian group, Asian group, population-based group, hospital-based group, IS group, CAD group, MI group (except for the recessive model), case control study group, and the subgroup of the cohort study group (except for the recessive model), respectively. For the association between the CETP TaqIB polymorphism and HDL-C, we also performed subgroup analysis based on ethnicity in the B1B1 vs. B2B2 model, B1B2 vs. B2B2 model, and B1B1 vs. B1B2 model. Significant associations were found between this variant and serum HDL-C concentrations in both the Caucasian and Asian group. These results further strengthen the conclusion that the CETP TaqIB-B2 allele protects against atherosclerosis by influencing HDL-C metabolism both in Asians and Caucasians. We also found that the association between CETP TaqIB-B2 polymorphism and composite ischemic CVD risk was stronger in Asians than Caucasians, but the relationship between the CETP TaqIB-B2 polymorphism and the HDL-C concentration in Asians was less consistent than that in Caucasians, which can be attributed to different environmental factors, lifestyle, etc.

Considering the influence of small-study effects on the overall results, we performed sensitivity analyses by excluding studies with low sample size or without the HWE. However, the corresponding pooled ORs and SMDs were unchanged in all comparisons, indicating statistically robust results.

Meanwhile, the existence of heterogeneity among the available studies, either for the CETP TaqIB polymorphism and composite ischemic CVD or for the CETP TaqIB polymorphism and HDL-C may affect the reliability of the results to a large extent. For the relationship between CETP TaqIB polymorphism and composite ischemic CVD, the heterogeneity can be explained by the source of controls (hospital controls and population controls) and ethnicity (Asians and Caucasians); for the relationship between CETP TaqIB polymorphism and serum HDL-C concentrations, the Galbraith plot was used to detect the source of heterogeneity for Asians and Caucasians. We identified four studies were as the main contributors of heterogeneity for Asians [74,76,77,80] and four for Caucasians [44,50,67,69]. The heterogeneity among Asians and Caucasians was effectively removed after excluding these outliers; however, the significant association between the CETP TaqIB polymorphism and serum HDL-C concentrations was unchanged. According to these outlier studies, the heterogeneity may be explained by the HWE, sample size, and disease.

There are several potential limitations in our present meta-analysis that should be acknowledged. First, there was significant heterogeneity in our study. Although we used appropriate meta-analytic techniques, we could not completely exclude the influence of the heterogeneity. Second, we may have missed eligible articles reported in other languages because our study only focused on articles published in English and Chinese. Third, the sample sizes of some studies were rather small. In summary, it is well-known that the composite ischemic CVD is affected by multiple environmental and genetic factors. Here, we discussed a single gene polymorphism and its impact on disease; however, several factors remain to be elucidated.

5. Conclusions

The present meta-analysis shows that the CETP TaqIB-B2 allele is associated with a higher serum HDL-C concentration and plays a protective role in composite ischemic CVD risk both in Asians and in Caucasians. Further investigations with the consideration of genetic and environmental interactions are needed.

Acknowledgments

This work was supported by grants from the National Science and Technology Support Projects for the “Eleventh Five-Years Plan” of China (No. 2009BAI82B04) and National Natural Science Foundation of China (No. 81560551).

Supplementary Materials

The following are available online at www.mdpi.com/1660-4601/13/9/882/s1, Figure S1: Meta-analysis of the composite ischemic CVD and the CETP TaqIB polymorphism (additive genetic model: B1B1 vs. B2B2). Figure S2: Meta-analysis of the composite ischemic CVD and the CETP TaqIB polymorphism (dominate genetic model: B1B1+B1B2 vs. B2B2). Figure S3: Meta-analysis of the composite ischemic CVD and the CETP TaqIB polymorphism (recessive genetic model: B1B1 vs. B1B2 + B2B2). Figure S4: Association between the CETP TaqIB polymorphism and HDL-C concentrations (B1B1 vs. B1B2). Figure S5: Association between the CETP TaqIB polymorphism and HDL-C concentrations (B1B2 vs. B1B2). Figure S6: Sensitivity analysis based on sample size for the associations between the CETP TaqIB polymorphism and HDL-C concentrations (B1B1 vs. B2B2). Figure S7: Sensitivity analysis based on Hardy–Weinberg equilibrium for the associations between the CETP TaqIB polymorphism and HDL-C concentrations (B1B1 vs. B2B2). Figure S8: Sensitivity analysis based on sample size for the associations between the CETP TaqIB polymorphism and HDL-C concentrations (B1B2 vs. B2B2). Figure S9: Sensitivity analysis based on Hardy–Weinberg equilibrium for the associations between the CETP TaqIB polymorphism and HDL-C concentrations (B1B2 vs. B2B2). Figure S10: Sensitivity analysis based on sample size for the associations between the CETP TaqIB polymorphism and HDL-C concentrations (B1B1 vs. B1B2). Figure S11: Sensitivity analysis based on Hardy–Weinberg equilibrium for the associations between the CETP TaqIB polymorphism and HDL-C concentrations (B1B1 vs. B1B2). Figure S12: Analysis of heterogeneity for Asian studies by Galbraith plot (B1B1 vs. B2B2). Figure S13: Analysis of heterogeneity for Caucasian studies by Galbraith plot (B1B1 vs. B2B2). Figure S14: Association between the CETP TaqIB polymorphism and HDL-C concentrations after exclusion of these outlier studies (B1B1 vs. B2B2). Figure S15: Association between the CETP TaqIB polymorphism and HDL-C concentrations after exclusion of these outlier studies (B1B1 vs. B1B2). Figure S16: Association between the CETP TaqIB polymorphism and HDL-C concentrations after exclusion of these outlier studies (B1B2 vs. B2B2). Checklist S1: PRISMA 2009 checklist. Table S1: MOOSE checklist.

Click here for additional data file. (2MB, pdf)

Author Contributions

Conceived and designed the experiments: Shuxia Guo and Minghong Yao. Performed the experiments: Yu-song Ding, Jing-yu Zhang, Yi-zhong Yan, and Jia-ming Liu. Analyzed the data: Mei Zhang, Dong-sheng Rui, and Qiang Niu. Contributed reagents/materials/analysis tools: Jia He and Heng Guo. Wrote the paper: Shuxia Guo, Minghong Yao, and Ru-lin Ma.

Conflicts of Interest

The authors declare no conflict of interest.

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