Introduction

A growing number of epidemiological studies indicate that coronary heart disease (CHD) has become a main cause of high morbidity and mortality worldwide [1]. With the improvement of living conditions and lifestyle in China, the incidence of CHD has continually increased over the years. In 2009, the mortality rate of CHD increased to 94.96/100,000 in the urban setting and 71.27/100,000 in rural China [2]. Researchers have shown that a variety of factors contribute to the pathogenetic process of CHD, including hyperlipidemia, hypertension, diabetes, and smoking. However, in recent years, a large number of studies have indicated that genetic factors play an important role in the pathogenesis of CHD [3]. Research on different populations and ethnicities indicated that patients whose first-degree relatives (<60 years old) with early onset CHD had a 2–10 times higher incidence of CHD compared with people who have no family history of CHD [4]. Therefore, genetic predisposition has gradually attracted attentions of researchers.

Paraoxonase 1 (PON1), located on the long arm of chromosome 7 at q21.3, plays an important role in antiatherosclerosis. Single-nucleotide polymorphism (SNP), the most common type of DNA sequence deviation, has been reported to account for approximately 90% of genetic variations in the human genome [5]. The genetic polymorphisms in the PON gene might affect the concentration and activity of PON enzyme in serum, thus, ultimately impacting enzyme function in vivo. Among all the SNPs in the PON1 gene, rs662 has been studied intensively by many researchers. The relationship between rs662 and susceptibility to CHD has been widely studied in Chinese population; however, the results have been inconsistent. Wang et al. [6] suggested that rs662 was significantly associated with susceptibility to CHD in North China; however, the study by Su et al. [7] came to the opposite conclusion. Xie et al. [8] reported that there was no significant impact of rs662 genetic variations on CHD in a southern Chinese population. Zhu et al. [9], however, indicated that CHD patients carrying rs662 were not significantly different from controls. To draw a precise conclusion on the relationship between rs662 and susceptibility to CHD, we conducted this meta-analysis.

Method

Search strategy

Two researchers respectively searched electronic search platforms, including PubMed, Embase, Wanfang Data, and Chinese National Knowledge Infrastructure (CNKI), to identify eligible studies published before July 2017. There was no restriction imposed on search language. The search terms were as follows: (1) PON, paraoxonase; (2) coronary heart disease, coronary artery disease, arteriosclerosis, myocardial infarction, ischemic heart disease, carotid atherosclerosis, atherosclerosis; (3) Chinese, China. All the terms were combined in the search.

Inclusion criteria

The following inclusion criteria were used: (1) case–control or cohort studies on the association between rs662 polymorphism and CHD; (2) providing the distribution data in patients and controls; (3) study describing a Chinese population. Exclusion criteria were (1) duplicate data, (2) incomplete rs662 distribution data, and (3) meta-analyses, letters, reviews, meeting abstracts, or editorial articles.

Data extraction

Two authors independently read the 14 studies that were included and extracted the following study characteristics: first author, year of publication, geographic area(s), ethnicity, sample size, distribution data in patients and controls.

Statistical analysis

We used pooled odds ratio (ORs) and 95% confidence intervals (CIs) to evaluate the strength of the association between the rs662 polymorphism and CHD. Heterogeneity in these studies was evaluated by χ2-based Q statistic test and I2 statistics. The fixed-effects model and random-effects model based on the Mantel–Haenszel method and the DerSimonian and Laird method were used to evaluate the sensitivity analysis. Publication bias by the method of Egger’s linear regression test was assessed by funnel plots. Stratified analyses were performed by ethnicity and geographic areas, including Han Chinese, South China, and North China. All data were analyzed with Review Manager (version 5.0.0), using two-sided P values.

Results

Description of included studies

The flow diagram for the literature selection is shown in Fig. 1. After searching the electronic search platforms, a total of 233 articles that studied the association between the rs662 polymorphism and risk of CHD were identified. Based upon the exclusion criteria, 219 studies were excluded, while 14 studies met the inclusion criteria. The characteristics of the included studies were summarized in Table 1. Thus, 4835 CHD patients and 5111 controls from 14 included articles were included in the present meta-analysis to evaluate the relationship between rs662 polymorphism and susceptibility to CHD in the Chinese population.

Fig. 1
figure 1

Flow diagram of study selection

Full size image
Table 1 Characteristics of the included studies
Full size table

Meta-analysis for the PON1 rs662 G>A polymorphism

In order to evaluate the precise association between the rs662 polymorphism and CHD risk, we compared the healthy group to the CHD group. In the total analysis, there was a significant association between rs662 and risk of CHD for all genetic models (G vs. A, OR 1.34, 95% CI 1.13–1.58; GG vs. AA, OR 1.72, 95% CI 1.25–2.36; GG+GA vs. AA, OR 0.74, 95% CI 0.60–0.90; GA+AA vs. GG, OR 1.48, 95% CI 1.14–1.93; Fig. 2). Furthermore, Figs. 3 and 4 showed, in the stratified analysis of ethnicity and geographic areas, the same results in the Chinese Han population (G vs. A, OR 1.30, 95% CI 1.09–1.54; GG vs. AA, OR 1.20, 95% CI 1.08–1.32; GG+GA vs. AA, OR 0.77, 95% CI 0.64–0.92; GA+AA vs. GG, OR 1.46, 95% CI 1.08–1.97) and the Southern Chinese population (G vs. A, OR 1.19, 95% CI 1.09–1.30; GG vs. AA, OR 1.40, 95% CI 1.17–1.68; GG+GA vs. AA, OR 0.80, 95% CI 0.70–0.91; GA+AA vs. GG, OR 1.25, 95% CI 1.06–1.47) for all genetic models. However, as illustrated in Fig. 5, no significant association was observed between rs662 and the population of North China (G vs. A, OR 1.39, 95% CI 0.97–1.98; GG vs. AA, OR 1.82, 95% CI 0.89–3.71; GG+GA vs. AA, OR 0.73, 95% CI 0.51–1.05; GA+AA vs. GG, OR 1.60, 95% CI 0.86–2.98). In addition, both in the total and the stratified analysis, the G allele suggested a higher susceptibility to CHD.

Fig. 2
figure 2

Association of the rs662 gene polymorphism on coronary heart disease susceptibility in the Chinese population. The association were assessed under four genetic models: a G vs A model, b GG vs AA model, c GA+AA vs GG model, d GG+GA vs AA model

Full size image
Fig. 3
figure 3

Association of the rs662 gene polymorphism on coronary heart disease susceptibility in Chinese Han. The association were assessed under four genetic models: a G vs A model, b GG vs AA model, c GA+AA vs GG model, d GG+GA vs AA model

Full size image
Fig. 4
figure 4

Association of the rs662 gene polymorphism on coronary heart disease susceptibility in South China. South China included Guangdong, Fujian, Shanghai, Hongkong, Jiangsu province. The association were assessed under four genetic models: a G vs A model, b GG vs AA model, c GA+AA vs GG model, d GG+GA vs AA model

Full size image
Fig. 5
figure 5

Association of the rs662 gene polymorphism on coronary heart disease susceptibility in North China. North China included Beijing, Liaoning, Hebei, Shandong, Xinjiang province. The association were assessed under four genetic models: a G vs A model, b GG vs AA model, c GA+AA vs GG model, d GG+GA vs AA model

Full size image

Publication bias

Begg’s funnel plot and Egger’s test were used to estimate publication bias. As shown in Fig. 6, there was no significant asymmetry in the funnel plot shapes.

Fig. 6
figure 6

Funnel plots for allele contrast of the rs662 polymorphism. The association were assessed under four genetic models: a G vs A model, b GG vs AA model, c GA+AA vs GG model, d GG+GA vs AA model

Full size image

Discussion

Currently, there are about 100 million cardiovascular patients in China; in addition, the mortality rate due to cardiovascular disease is significantly higher than that of cancer and other diseases. It is estimated that about 10,000 people die of cardiovascular disease every year in China [18]. A large number of researchers have suggested that the main mechanisms of CHD pathogenesis include lipid infiltration, chronic inflammation, and oxidation [19,20,21]. However, CHD is a complex disease with multiple factors that work together leading to the pathogenesis of the disease. Convincing evidence, recently, has emerged to indicate that individual susceptibility to CHD might be partially determined by genetic predisposition.

Paraoxonase 1 (PON1), a glycoprotein synthesized in the liver and secreted into the blood, might take part in the pathogenesis of arterial thrombosis and atherosclerosis [22]. There are approximately 200 single nucleotide polymorphisms (SNPs) in the human PON1 gene. Rs662 is one SNP in the PON1 gene, which has attracted much attention from researchers. Large numbers of studies have researched the relationship between rs662 and the risk of CHD. However, recent results have been inconsistent. Therefore, we performed this meta-analysis to conduct a more precise estimate.

This is the first meta-analysis to evaluate the association of rs662 with CHD in the Chinese population. There were 14 studies, including 4835 CHD patients and 5111 controls in our meta-analysis. In the total analysis, there was a significant association of rs662 with susceptibility to CHD in China. G allele carries have a higher risk of CHD. In the subgroup analysis, the same result was also observed in Chinese Han and South China, but not in North China. In addition, the HWE data in the control and CHD patients groups suggest that there is no significant genetic background differences between the participants. The reliability and stability of the meta-analysis were examined by sensitivity analysis. In all, the results of our meta-analysis provide strong evidence for the association between the rs662 polymorphism and susceptibility to CHD in the Chinese population.

Our present study has demonstrated that there is an association between the rs662 polymorphism and risk of CHD; however, there are several limitations. First, the number of cases and controls included in our study is relative small, so there is insufficient statistical power to investigate the association between the rs662 polymorphism and risk of CHD. Second, the results of our study are only applicable to China because data from Chinese patients were included. Third, the heterogeneity in the study was high, and a stratification analysis was not possible due to the limited data of the included studies.

Taken together, our study provides evidence that the single nucleotide polymorphism rs662 has a significant association with susceptibility to CHD; the G allele might be the risk allele. Furthermore, studies with a larger number of patients with an association between rs662 and CHD are required to confirm the present findings.