Essay Example on Coronary artery disease CAD is a Complex Trait








Coronary artery disease CAD is a complex trait caused by a number of genetic and environmental factors CAD remains a leading cause of death in most developing countries According to estimates by the World Health Organization WHO nearly seven million people worldwide die of CAD each year equally among men and women with most of these deaths occurring in both high and low income countries 1 The prevalence of CAD worldwide is rapidly rising Over the past twenty years CAD has become the leading cause of death in Kingdom of Saudi Arabia KSA and has reached epidemic proportions Mortality rates associated with CAD have shown an exceptional increase particularly in fast developing economies like the KSA The maximum increase of coincided with fast economic growth and urbanization that promotes sedentary lifestyle high energy fat food smoking low intake of fruits and vegetables and mainly developing of oxidative stress These factors have undoubtedly contributed to the epidemic of CAD in KSA 2 More than 80 of sudden cardiac deaths are caused by atherosclerotic CAD Atherosclerosis is characterized by the buildup of fatty lesions inflammation and scarring of arterial walls with oxidative stress as a primary contributing factor Atherosclerosis is an inflammatory disease

According to response to retention hypothesis the whole sequence of events is found to be initiated by the retention of modified Low density lipoprotein LDL 3 The oxidative modifications of LDL in the arterial wall may play major role in the development of atherosclerotic lesions Oxidative stress is known to increase the formation of oxidized LDL So many studies suggested that LDL acts as a key event in the genesis of atherosclerosis 4 Epidemiological pharmacological genetic and clinical studies implicated that the development of atherosclerosis is closely associated with so many extrinsic and intrinsic risk factors including age hypertension obesity smoking lack of exercise diabetes and dyslipidemia have been identified Atherogenic dyslipidemia is characterized by abnormal levels of cholesterol triglycerides and LDL however a low level of high density lipoprotein HDL is a risk factor for the development of CAD and stroke 5 Several authors are indicated that development and progression of CAD is related to free radical processes Lipid peroxidation is the oxidative degradation of lipids It is the process in which free radicals steal electrons from the lipids in cell membranes resulting in cell damage disruption of proteins and other cell components which is potentially harmful because it s uncontrolled A lot of oxygenated compounds particularly aldehydes such as Malondialdehyde MDA are produced during the attack of free radicals to membranes lipoprotein and polyunsaturated fatty acids 6

Thus monitoring of lipid profiles and lipid peroxidation in the blood provides useful information for the prognosis of CAD patients The paraoxonases PON are enzymes involved in oxidative stress in the atherosclerosis process and consequently in vascular disease The PON gene family in mammals includes 3 members PON1 PON2 and PON3 are basically lactonases with one of the broadest known substrate specificities All 3 PONs metabolise 5 hydroxy cicosate traeomic acid 1 5 lactone and 4 hydroxy docosahexaenoic acid which are derived from arachidonic acid PON1 and PON3 are found in many tissues as well as in circulation associated with HDL C while PON2 is exclusively intracellular All PONs share approximately 70 identity at the nucleotide level and 60 identity at the aminoacid level and are located adjacent to each other on chromosome 7 7q21 3 22 1 in humans 7 8 Human serum PON1 is a 44 kDa 355 amino acids calcium dependent glycoprotein predominantly expressed in the liver that circulates bound to HDL particles PON1 is an esterase that catalyzes the hydrolysis of multiple organophosphates including paraoxon diazoxon sarin and soman and aryl esters such as phenyl acetate PON1 became the focus of intense research both at phenotypic and genetic levels subsequent to the identification of its antioxidant properties particularly to protect LDL from oxidative damage 9

The most studied PON1 gene polymorphism result from amino acid substitutions at positions 192 Glutamine Q Arginine R in the coding region of the gene Alleles at the 192 Q and R allele loci of the PON1 codon have been associated with enzyme activity and concentration respectively The QQ genotype exhibits a low PON activity low activity phenotype while RR genotype exhibits a high PON activity high activity phenotype However there is also marked variation in enzyme activity between individuals of the same genotype 10 PON1 position 192 R isoform binds with HDL with a 3 fold lower affinity than the Q isoenzyme and consequently exhibits reduced stability lapolactonase arylesterase activity It has been suggested that the Q allele which is more abundant than the R allele is responsible for the protective effect against atherosclerosis whereas the R allele has been related to CAD because of less protection against LDL These differences in the properties of PON1 192 Q R isoenzyme provide the basis for the contribution of 192 Q R polymorphism to the susceptibility to atherosclerosis 11 So many authors revealed that PON1 Q192R polymorphism are an important risk for MI and CAD populations 12 13 Contrastingly some studies reported that no such association between Q192R polymorphism and an elevated atherosclerosis risk 14 Moreover several studies have indicating that it is an important to determine the phenotype not just the genotype when studying the atherosclerosis 15 16 Thus in this case control study we assess the lipid profile lipid peroxidation product MDA the distribution and frequency of PON1 Q192R polymorphism and the concerned phenotype arylesterase activity was analyzed with the risk of CAD and healthy controls in the population of the central province of Saudi Arabia

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