Endothelial Nitric Oxide Synthase G894T Gene Polymorphism and Ischemic Heart Disease among Smokers: A Pilot Study

Abstract

Cardiovascular diseases are one of the most common causes of morbidity and mortality globally. It is responsible for 47% of deaths in Egypt. Ischemic heart disease is an inflammatory process in which immune mechanisms interact with metabolic risk factors to initiate, propagate and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. However, that optimistic prediction has needed revision. The disease may be asymptomatic, may manifest in the form of angina pectoris, acute myocardial infarction or even sudden death. Diagnosis is confirmed by ECG, elevated cardiac markers and imaging techniques. The molecular etiology of coronary atherosclerosis involves interaction of many genes and environmental factors. Various genetic polymorphisms have been linked to the atherosclerotic process and its complications. Nitric oxide is a soluble gas with a very short half -life that is synthesized and released in a continuous fashion in our body and it is considered the most important molecule produced by the vascular endothelium. It has many activities that play a major role in vascular homeostasis including vascular relaxation, inhibition of platelet and leukocyte adhesion to the vascular wall and inhibition of proliferation of smooth muscles. It is also protective against atherosclerotic changes. Decreased NO activity facilitates vascular inflammation and formation of foam cells. Synthesis of NO is mediated by the action of the enzyme NOS. NOS enzyme has three isoforms; iNOS, nNOS and eNOS. Endothelial NOS is mainly expressed in the vascular endothelium, also detected in platelets and cardiac muscles. Many environmental factors may affect eNOS activity like cigarette smoking and aging. NOS3 gene encodes the protein eNOS and is located on the long arm of chromosome 7 and it is thought to play an important role the in the pathogenesis of IHD. NOS3 gene is a highly polymorphic gene, and since the physiological functions of NO are very diverse, the effects of NOS3 polymorphism are being investigated in association with several diseases and conditions. The polymorphism of interest in this study is Glu298Asp polymorphism. The guanine to thymine (Glu298Asp) polymorphism at position 894 of the eNOS gene {replacement of glutamate (G) by aspartate (T)} is under extensive study and T allele had been described as susceptibility allele for CAD and wild type homozygosity (GG genotype) might be protective in some diseases. We conducted this study to assess the association between G894T Gene Polymorphism and Ischemic Heart Disease among Smokers. Eighty subjects were included in this study. Half of them were IHD patients, while the second half were healthy individuals. We subdivided each group into half smokers and another half non smokers. Our results revealed higher frequency of DM, hypertension and positive family history of ischemic heart among cases compared to controls. Although there was no significant difference between the cases and controls regarding the number of cigarette packs smoked per day, IHD patients smoked for a significantly higher number of years compared to the controls. Also, IHD patients showed a significantly higher smoking index. There was no statistically significant difference as regards NOS3 gene G894T genotypes between case and control groups. Considering the T allele as the risky allele, we tried to study its influence on the clinical data of both cases and controls. The results revealed that smoking doesn’t increase risk of IHD among the T allele carriers. Several studies have investigated the relationship between G894T Gene Polymorphism and the risk of IHD; some confirmed the association while others denied it. The different and conflicting conclusions may arise from the different genetic susceptibility of the different ethnic groups.