LINKAGE ANALYSIS BY A TRANSMISSION / DISEQUILIBRIUM TEST OF RUSSIAN SIBLING PAIRS WITH CORONARY ARTERY DISEASE
Tupitsina TV1,*, Slominsky PA1, Yufereva YM2, Perova NI2, Aronov DM2, Limborska SA1
*Corresponding Author: *Corresponding Author: Dr. Tatiana V. Tupitsina, Department of Human Molecular Genetics, Institute of Molecular Genetics of Russian Academy of Sciences, Kurchatov sq. 2, 123182, Moscow, Russia; Tel.: +007-499-1960210; Fax: +007-499-1960221; E-mail: tanya_tupitsina@mail.ru
page: 43

INTRODUCTION

 

Atherosclerosis, the primary cause of coronary artery disease (CAD), is the leading cause of human morbidity and mortality in industrialized and developing countries [1]. The etiology of CAD is multifactorial, with many genetic and environmental determinants, including cigarette smoking, alcohol consumption, diabetes mellitus, obesity, aging, elevated blood pressure, elevated serum levels of low-density lipoprotein-cholesterol (LDL-C) and low serum levels of high-density lipoprotein-cholesterol (HDL-C).

Several candidate genes could determine individual susceptibility of blood vessels in the myocardium to develop atherosclerosis and CAD; a number of gene poly morphisms associated with an elevated risk of myocardial infarction (MI) have now been identified [2-4]. Numerous studies have revealed associations between elevated blood pressure and CAD, and many candidate genes, particularly members of the renin-angiotensin system, have been investigated [5-10]. Both linkage and association studies have provided strong evidence for the role of the angiotensino gen (AGT) gene in hypertension in different populations [11-13]. The angiotensin-converting enzyme (ACE) gene plays a key role in the renin-angiotensin system and is associated with CAD [14]. The insertion/deletion (I/D) polymorphisms in the 16th intron of the ACE gene were identified in 1990 [15]. Analysis of ACE levels in the blood plasma of individuals of various populations demonstrated that homozygotes for the D allele had the highest ACE activity [14,16] and were at higher risk of developing MI and CAD [14,17].

The most significant risk factors for CAD are related to lipoprotein metabolism. Plasma lipoprotein disturbances are among the most common biochemical abnormalities observed in patients with CAD [18]. The HDL-C level is strongly inversely correlated with developing CAD [19, 20]. This antiatherogenic property of HDL is mainly due to its role in reverse cholesterol transport. The ATP binding cassette transporter 1 (ABCA1) protein has been identified as a mediator of cholesterol efflux [21,22]. ABCA1 stimulates cholesterol and phospholipid efflux to apolipo protein A1 (the main component of HDL) and may act as a cholesterol/phospholipid flippase at the plasma membrane level (for reviews see [23,24]).

Several common polymorphisms have been reported in the coding and promoter regions of the ABCA1 gene [25,26]. Some are associated with altered plasma lipid levels and with the development of CAD. For example, the R219K polymorphism is associated with progression of atherosclerosis and with elevated triglyceride (TG) and HDL-C levels in familial hypercholesterolemia patients from Spain [27]. Other single-nucleotide polymorphisms in the coding region had milder effects on plasma lipids and atherosclerosis [25].

Nitric oxide (NO) is a cell signaling molecule that plays an important role in physiological processes such as regulation of the vascular system, neurotransmission and various homeostatic events. It may exhibit either athero genic or atheroprotective effects, depending on its source. Thus, the vasodilator function of NO produced by endothelial NO synthase (eNOS) is protective. Deletion of the eNOS gene in a background of apoE deficiency gene in a background of apoE deficiency results in hypertension and increased atherosclerosis [28]. Several polymorphisms have been found in the eNOS gene [29], and some have been associated with increased cardiovascular risk [30,31].

Ephrins (EFNs) are cell-surface ligands of ephedrine receptor tyrosine kinases. They are classified into A and B subfamilies; EFNBs comprise three transmembrane proteins (EFNB1-3), which are capable of reverse transmission of signals into cells. Such functions are well demonstrated in the central nervous system, during angiogenesis and in intestinal development and remodeling [32-36]. EFNB3 plays a role in cardiovascular development [34].

In this study, we analyzed polymorphisms in the genes for ABCA1, ACE, AGT, eNOS and EFNB3 in 85 Russian patients with angiography-proven CAD and 100 of their siblings.





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