Coronary artery disease (CAD), especially acute myocardial infarction, is becoming one of the major causes of morbidity and mortality worldwide [1]. Multiple factors, such as genetic variants, lifestyle and environmental factors, are believed to be involved in the occurrence and progression of CAD [2, 3, 4]. In recent years, more and more researchers carry out large scale genomewide association studies (GWAS) to elucidate the pathogenesis of CAD at the gene expression level and the results have demonstrated that gene polymorphisms are strongly associated with the susceptibility to CAD [5,6].
Osteoprotegerin (OPG), a new member of the tumor necrosis factor (TNF) receptor superfamily, has been identified as a soluble non-transmembrane glycoprotein secreted by osteoblasts (OCs) [7]. It plays a key role in the formation and resorption of bone through inhibiting differentiation and maturation of OC and inducing OC apoptosis [8]. In addition, OPG is also an important vascular modulator and strongly linked with the occurrence and progression of atherosclerosis and arteriosteogenesis [9]. More importantly, OPG has been associated with the presence and severity of CAD, as evidenced by elevated serum OPG concentrations in CAD patients [10,11].
The gene encoding OPG is located on the long arm of chromosome 8 at position 24. Some recent studies have shown that the T950C and G1181C polymorphisms of the
A systematic search assembling the following terms: genetic polymorphism, single nucleotide polymorphism, gene mutation, genetic variants, coronary atherosclerosis, myocardial ischemia, acute coronary syndrome, coronary artery disease, myocardial infarction, ischemic heart disease, TNFRSF11B, osteoprotegerin, was conducted in PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Chinese Wan Fang databases up to May 1 2017 to identify all potentially relevant studies. Hand-searching was carried out to determine other potential eligible studies through scanning the references cited in the retrieved articles. The full-text articles were further reviewed to determine whether they were included in the final analysis strictly based on eligibility criteria. If two reviewers disagreed, all the authors critically evaluated the studies to judge of the inclusion or exclusion of a certain study.
All the eligible articles were supposed to meet the following major inclusion criteria:
Data extraction was performed independently by two authors using a standardized data extraction form including following elements:
First, the genotype frequencies of the
As shown in Figure.1, 36 potentially eligible records were initially identified through literature search. Thirty articles were excluded, including seven articles that were duplicated, five articles that were reviews, 12 articles that did not involve CAD, four articles that did not conform to the diagnostic criteria of CAD, one article that lacked normal controls, and one article that did not provide sufficient data for the distribution of the genotype. Finally, six articles in accordance with the inclusion criteria were included in this meta-analysis [12, 13, 14, 15, 16, 19]. To be specific, two studies involved the G209A polymorphism, three studies with T245G polymorphism, three studies with T950C polymorphism, and five studies with G1181C polymorphism.
Flow diagram of the study selection process.Figure 1
The characteristics of the included studies are summarized in Table 1. Overall, four studies were conducted in Asians, and the other two studies were carried out in Caucasians. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the gene polymorphisms in five out of six studies. The average score of NOS was at 9. The genotype distribution of the controls in all studies was consistent with HWE.
Main characteristics of studies included in the meta-analyses. NA: not available; CAD: coronary artery disease; ACS: acute coronary syndrome; PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism; HWE: Hardy-Weinberg equilibrium.Studies [references] [15] [14] [19] [12] [13] [16] Country Poland China China Germany Japan China Ethnicity Caucasian Asian Asian Caucasian Asian Asian Number (case/control) 31/30 184/68 178/312 522/468 405/126 222/146 Age, year (case/control) 65.6/70.5 62.6/60.79 58.3/57.2 NA 63.0/59.0 70.1/63.7 Male% (case/control) 0.0/0.0 79.3/57.4 64.0/62.5 100.0/100.0 NA 72.5/59.6 Hypertension% (case/control) NA NA 68.5/56.7 NA 63.0/51.0 77.0/65.8 Study type case-control case-control case-control case-control case-control case-control Primary outcome CAD ACS CAD CAD CAD CAD Genotyping method PCR-RFLP Sanger sequencing PCR-RFLP PCR-RFLP PCR-RFLP PCR-RFLP NOS score 9 9 9 9 9 9 HWE test (control) yes yes yes yes yes yes
Meta-analysis of the G209A polymorphism was involved with two studies consisting of 215 CAD cases and 98 controls. There was no association between the G209A polymorphism and the risk of CAD when pooling all the data in the meta-analysis (AA/AG
Forest plots for Figure 2
Main results of the meta-analyses of the pooled odds ratios. ORb: crude odds ratio; 95% CI: 95% confidence interval; Ph: p value for Chochran’s Q test between study heterogeneity in each genetic comparison model; a: fixed effects model was used for all of the above; NA: not available.Variable Cases/Controls ( ORb (95% CI) Ph Value 1 11 12 (11 or 12) 11 G209A (1=A; 2=G) 215/98 1.128 (0.664-1.916) 0.655a NA 0.898 (0.500-1.613) 0.718a 1.005 (0.564-1.792) 0.986a NA T245G (1=T; 2=G) 393/410 0.940 (0.678-1.302) 0.708a 0.679 (0.236-1.957) 0.474a 0.628 (0.209-1.886) 0.407a 0.664 (0.247-1.785) 0.417a 0.979 (0.682-1.405) 0.909a T950C (1=C; 2=T) 1137/1024 1.264 (1.108-1.442) 0.000a 1.615 (1.242-2.100) 0.000a 1.227 (0.994-1.515) 0.057a 1.327 (1.090-1.617) 0.005a 1.376 (1.097-1.726) 0.006a G1181C (1=C; 2=G) 1105/906 1.203 (0.957-1.514) 0.114 1.139 (0.677-1.917) 0.623 1.243 (1.027-1.504) 0.026a 1.268 (1.064-1.511) 0.008a 1.227 (0.943-1.595) 0.127a
The result of the sensitivity analysis showed that the pooled ORs of the G209A, T245G, T950C and G1181C polymorphisms were not considerably affected by eliminating any individual study (Figure 3). The funnel plots were symmetrical by visual inspection (Figure 4) and Egger’s test also suggested no publication bias (
Sensitivity analysis results. (A) Sensitivity analysis for G209A polymorphism and the risk of CAD under dominant (AA/AG Figure 3
Evaluation for publication bias. (A) Funnel plot for G209A polymorphism and the risk of CAD under dominant (AA/AG Figure 4
Osteoprotegerin has been considered as a novel biomarker for predicting prevalence and severity of CAD [20]. Jono
G1181C is the most controversial in all polymorphisms of the
The T950C polymorphism is located 233 bp upstream from the translation initiation site in the promoter region, and it could derive its functional significance by altering the promoter activity [13]. Previous research has demonstrated that T950C is the only polymorphism that is associated with serum OPG levels [12]. Our meta-analysis indicated that the T950C polymorphism was remarkably linked with the risk of CAD, which was consistent with previous results [12]. Moreover, we also reported that no association existed between G209A and T245G polymorphisms and the risk of CAD, which was in line with previous studies [14, 15, 19].
Similar to other meta-analyses, several limitations existed in our meta-analysis. First, the sample size is still relatively small and may not provide sufficient statistical power to estimate the correlation between the
Secondly, we did not evaluate the potential publication bias that may influence the result. Finally, although little heterogeneity exists, subgroup analysis should be performed to assess the association between the
In conclusion, to the best of our knowledge, this meta-analysis