Abstract
Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs.
Highlights
Cardiovascular diseases (CVDs) encompass all diseases of the heart and blood vessels
Among 1632 outpatients, we selected 315 outpatients divided into two groups: 171 unrelated normotensive normocholesterolemic healthy cases without any family history of coronary artery disease (CAD) or stroke or hypertension or hypercholesterolemia ranging in age from 21 to 78 years defined here as the “Healthy group”, and 144 unrelated hypertensive hypercholesterolemic subjects ranging in age from 21 to 81 years defined here as the “HH group”
The frequencies of 7 polymorphisms known to be implicated in thrombosis were: prothrombin FII G20210A (6.4%), FVR2 (16.4%), FVL (17.0%), factor XIII (FXIII) V34L (41.5%), methylenetetrahydrofolate reductase (MTHFR) C677T (57.9%), MTHFR A1298C (62.6%), and Plasminogen activator inhibitor type-1 (PAI-1) 4G allele (78.9%) (Fig 1B)
Summary
Cardiovascular diseases (CVDs) encompass all diseases of the heart and blood vessels They include coronary heart diseases, heart valves diseases, cardiomyopathies, heart rhythm disorders, cerebrovascular diseases and congenital diseases such as heart defects and lower limb arterial disease. Atherosclerosis is a disease characterized by deposits of fat (mostly cholesterol), cells and other substances in the lining of the arteries of large and medium caliber. This disease causes more morbidity and mortality in the western world than any other disorder. Given the pathophysiological role of this system and the well established benefits of the ACE inhibitors [13], it has been suggested that genetic variants affecting the function of this system may be considered as genetic risk factors for cardiovascular diseases. Other genes like β-fibrinogen, HPA-1, Apo B and Apo E have been implicated in atherosclerosis
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