Four genetic polymorphisms of paraoxonase gene and risk of coronary heart disease: A meta-analysis based on 88 case–control studies
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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Both authors have contributed equally to this study, and should be considered as co-first authors.