The relationship between paraoxonase1-192 polymorphism and activity with coronary artery disease

Abstract

Objective

We tested the association between PON1 polymorphism, PON1 activity, oxidative susceptibility of LDL and coronary artery disease in Egyptians.

Methods

PON1 polymorphism, serum PON1 activity, lipoprotein oxidation susceptibility and lipid profile were measured.

Results

Levels of HDL and paraoxonase activity were significantly decreased in CAD patients compared to control group, and in patients with three vessels compared to those of single or two vessels disease. High-activity allele (R) has a more atherogenic lipid profile than for the low activity allele (Q). PON1 RR genotype has nine fold risks to develop CAD in Egyptians while those with PON1 QR genotype have four fold risks.

Conclusion

The PON1 activity is lower in subject with CAD and there is a significant relationship between activity of PON1 and the severity of coronary atherosclerosis. Also, we provide evidence of a significant association between R allele of the PON1 polymorphism and the development of coronary artery disease.

Introduction

Oxidative stress plays a crucial role in the development of atherosclerosis by oxidation of low-density lipoprotein (LDL) that subsequently leads to formation of foam cells. Conversely, high-density lipoprotein (HDL) is a well-known anti-oxidant molecule that prevents atherosclerosis [1]. HDLs can protect LDLs from oxidative damage. The antioxidant effect of HDLs is determined by its enzymes, in particular paraoxonase, an HDL-associated enzyme capable of hydrolyzing lipid peroxides [2].

Paraoxonase (PON1) is a 44 kDa Ca²⁺-dependent glycoprotein, synthesized in the liver and is located on the surface of high density lipoprotein (HDL). Recently, it has been shown that PON1 decreases generation and accumulation of lipoperoxides in LDL. In addition, PON1, by destroying oxidized phospholipids, reduces the ability of oxidized LDL to induce monocyte binding and transmigration and thus, inflammation in the vessel wall [3]. In knockout mice lacking the gene for PON1, atherosclerosis develops more rapidly than in wild-type mice, whereas mice that overexpress human PON1 are resistant to atherosclerosis [4]. Thus, PON1 may be involved in protection against atherosclerosis. The role of PON1 may be particularly meaningful because oxidized LDL promotes secretion of the potent endothelial constrictor, endothelin, and reverses the impairment of endothelium-mediated vasodilatation in stenotic vessel [5].

Besides its protective effects against LDL peroxidation, HDL-associated paraoxonase has been demonstrated to inhibit the oxidative damage of HDL as well. The oxidation of HDL not only reduces its capability to prevent the oxidative modification of LDL, but also diminishes the ability of HDL to function as a potent acceptor for cholesterol efflux [6].

PON1 enzyme activity for paraoxon as a substrate is modulated by a number of polymorphisms at the PON1 gene located in chromosome 7q21.3, which is clustered with at least two other related genes, paraoxonase2 and paraoxonase3 [7]. Paraoxonase (A/G) polymorphism results in glutamine (Q) to arginine (R) substitution at codon 192. This 192Q isoform has been related to lower paraoxonase (paraoxon-hydrolyzing) and arylesterase (phenylacetate-hydrolyzing) activity, and 192 R, an isoform with high activity toward paraoxon hydrolysis [8].

Although PON1 activity and concentration are determined genetically, various factors, such as diet, lifestyle, and environmental factors, can influence PON1 activity and/or concentration. Degraded cooking oil has been reported to lower serum PON1 levels in humans. Dietary polyphenols increase PON1 activity, as does moderate alcohol intake. Smoking is known to decrease serum PON1 activity. Recent evidence shows that exposure to environmental chemicals can inhibit PON1 activity. Furthermore, low serum PON1 activity independent of genotype has been reported in diseases associated with accelerated atherogenesis, such as diabetes mellitus, hypercholesterolemia, and renal failure [4].

Whereas some authors have failed to find a link between the variation in paraoxonase gene and changes in lipoprotein concentrations [9], [10], others have found a significant association between paraoxonase-192 genetic variants and changes in HDL-cholesterol levels and in triglyceride concentrations in relatively genetically isolated populations [11], [12] Therefore, at present the relationship between paraoxonase genetic polymorphism and atherosclerosis is unclear. Whether the paraoxonase gene can modulate the lipid profile is a matter of conjecture, but remains a possibility in the light of the above population studies.

Because PON1-192 genetic polymorphism strongly influences PON1 activity and does vary between different ethnic groups, we tested the association between this polymorphism, PON1 activity, changes in oxidative susceptibility of LDL and coronary artery disease (CAD) in Egyptian patients.