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
life style, 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.
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
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
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.
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 docos ahexanoic
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.
serum PON1 is a 44- kDa (355 amino acids) calcium dependent glycoprotein,
predominately 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 arylesters 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.
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.
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.