Elsevier

Atherosclerosis

Volume 214, Issue 2, February 2011, Pages 377-385
Atherosclerosis

Four genetic polymorphisms of paraoxonase gene and risk of coronary heart disease: A meta-analysis based on 88 case–control studies

https://doi.org/10.1016/j.atherosclerosis.2010.11.028Get rights and content

Abstract

Objective

The human paraoxonase (PON) is calcium dependent HDL associated ester hydrolase which has attracted considerable attention as a candidate gene for coronary heart disease based on its enzyme function as a key factor in lipoprotein catabolism pathways. Many studies have examined the association between polymorphisms in the PON gene and risk of coronary heart disease (CHD), but the results have been inconsistent.

Methods

We conducted a meta-analysis of 88 studies on 4 PON polymorphisms [Q192R, L55M, and T(−107)C in the PON1 and the S311C in the PON2] published before August 2010, including a total of 24,702 CHD cases and 38,232 controls. We also systematically explored potential sources of heterogeneity.

Result

In a combined analysis, the summary per-allele odds ratio for CHD of the 192R was 1.11 (95% CI: 1.05–1.17). However, when the analyses were restricted to 10 larger studies (n > 500 cases), the summary per-allele odds ratio was 0.96 (95% CI: 0.90–1.02). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the 55M, (−107)T, and 311C variant showed no significant overall association with CHD, yielding a per-allele odds ratio of 0.94 (95% CI: 0.88–1.00), 1.02 (95% CI: 0.91–1.15) and 1.02 (95% CI: 0.90–1.16) respectively.

Conclusions

This meta-analysis suggested an overall weak association between the R192 polymorphism and CHD risk.

Introduction

Coronary heart disease (CHD), including its most severe complication, myocardial infarction (MI), is the leading cause of morbidity and mortality worldwide. Despite advances in our understanding of cardiovascular disease, detailed pathogenetic mechanisms of CHD remain a matter of speculation. Evidence is increasing that predisposition to CHD is associated with oxidative stress. Thus, the enzymes involved in their physiological metabolisms have received a great deal of attention.

Paraoxonase (PON) is a multifunctional antioxidant enzyme that not only can detoxify insecticides, nerve gas, but also can destroy oxidized low-density lipoprotein (ox-LDL). The PON gene cluster, located on chromosome 7q21.3–22.1, contains at least 3 members with about 65% similarity at the amino acid level (PON1, PON2 and PON3) [1]. Serum paraoxonase (PON1) is a 44-kDa Ca2+-dependent glycoprotein enzyme, synthesized in the liver and bound to the surface of high-density lipoproteins (HDLs). PON1 has been demonstrated to be a major contributor to the antioxidative properties of HDL, partially explaining the protective role of HDL against atherosclerosis [2], [3]. PON3 has been identified as a lactonase associated with HDL and could co-operate in the prevention of LDL oxidation [4]. PON2 also has antioxidant properties, but unlike PON1 and PON3, which are expressed primarily in the liver; it is ubiquitously expressed, especially in endothelial and human aortic smooth muscle cells [5].

Several polymorphisms in the exons and promoter region of the PON1 and PON2 genes have been investigated in numerous studies for their association with CHD. The PON1 gene has 2 common polymorphisms in the coding region, which lead to a glutamine  arginine substitution at position 192 (Q192R) and leucine  methionine substitution at position 55 (L55M). The T to C exchange in position −107 is one of the several polymorphisms identified in the promoter region of PON1. The T to C exchange in the promoter region −107 of the PON1 gene (C-107T) that has been identified as an independent genetic risk factor for cardiovascular disease in type 2 diabetic patients [6]. A common polymorphism at codon 311 (C311S) in the PON2 gene also has been reported to be associated with the risk of CHD in many studies.

In the past decade, several studies have investigated the associations between the polymorphisms of PON gene cluster and CHD susceptibility. However, these studies have yielded apparently conflicting results. Such inconsistency could be due partly to insufficient power, the small effect of the polymorphism on CHD risk and false-positive results. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between paraoxonase gene polymorphisms and CHD risk.

Section snippets

Literature search and data extraction

Genetic association studies published before the end of August 2010 on CHD and at least 1 of the 4 polymorphisms in the PON gene described above were identified through a search of PubMed, EMBASE, Web of Science, and CNKI (Chinese National Knowledge Infrastructure) without language restrictions. Search term combinations were keywords relating to the paraoxonase genes (e.g., “paraoxonase”, “PON”, “PON1”, and “PON2”) in combination with words related to CHD (e.g., “coronary heart disease”,

Characteristics of studies

A total of 88 eligible association studies were identified [6], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [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], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83]

Discussion

Large sample and unbiased epidemiological studies of predisposition gene polymorphisms could provide insight into the in vivo relationship between candidate genes and complex diseases. The present meta-analysis provides the most comprehensive assessment of the risk of CHD and four linked variants related to paraoxonase genes. Its strength was based on the accumulation of published data giving greater information to detect significant differences. In total, the meta-analysis involved 88 studies

Conflict of interest statement

We declare that we have no conflict of interest.

Acknowledgement

This work was supported by National Natural Science Foundation of China (30772157).

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