Abstract
The human paraoxonase (PON) gene cluster is comprised of three contiguous genes (PON1, PON2 and PON3) of presumably common origin coding three lactonases of highly similar structure and substrate specificity. The catalytic activity of PON proteins is directed toward artificial organophosphates and in physiological conditions toward thiolactones and oxidized phospholipids. Consequently, PON enzymes are regarded as an effective defense against oxidative stress and, as a result, against atherosclerosis development. Additionally, both PON’s serum activity and its concentration are influenced by several polymorphic variations in coding and noncoding DNA regions of the PON gene cluster remaining in linkage disequilibrium. Hence, the genetic polymorphism of the PON gene cluster may contribute to atherosclerotic process progression or deceleration. In this review the authors analyzed the relevance of noncoding DNA polymorphic variations of PON genes in atherosclerosis-related diseases involving coronary and peripheral artery disease, stroke, diabetes mellitus, dementia and renal disease and concluded that the effect of PON gene cluster’ polymorphism has a considerable impact on the course and outcome in these conditions. The following PON genetic variations may serve as additional predictors of the risk of atherosclerosis in selected populations and individuals.
Highlights
The paraoxonase gene cluster consists of three genes (PON1, PON2, PON3) localized on the long arm of chromosome 7 between q21.3 and q 22.1 [1] and comprises summarily 136 KB arranged in order PON1, PON3 and PON2 [2]
Because the essential physiological function of PON enzymes may be the hydrolysis of lipids peroxides and homocysteine thiolactones contributing to atherosclerosis development, it was assumed that individuals characterized the by genotype associated with the possible lower PON protein concentration and activity would be more prone to atherosclerosis
It is well documented that diabetes increases the risk of atherosclerosis development and facilitates atherosclerotic complications [110], so the possible relationship between PON gene cluster polymorphisms and diabetes became a subject of current interest
Summary
The paraoxonase gene cluster consists of three genes (PON1, PON2, PON3) localized on the long arm of chromosome 7 between q21.3 and q 22.1 [1] and comprises summarily 136 KB arranged in order PON1, PON3 and PON2 [2]. Taking into consideration that polymorphic variations of the PON cluster gene directly affect PONs’ activity, concentration and the binding regulatory elements it is reasonable to believe that they may contribute to atherosclerosis–related diseases, such as coronary artery disease, stroke, peripheral artery disease, diabetes mellitus, dementia and renal disease. This issue is worth of discussing since both, the PON genotype and enzyme activity, may serve as possible predictors of the clinical forms of atherosclerosis [40]
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