A Functional variant of the iNOS gene flanking region is associated with LAD coronary artery disease: an autopsy study

• Published in: European journal of clinical investigation Vol. 33; no. 12; pp. 1032 - 1037
• Main Authors: Kunnas, T. A., Mikkelsson, J., Ilveskoski, E., Tanner, M. M., Laippala, P., Penttilä, A., Perola, M., Nikkari, S. T., Karhunen, P. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2003; Blackwell
• Subjects: Adult; Age Distribution; Aged; Biological and medical sciences; Cardiology. Vascular system; Coronary artery disease; Coronary Artery Disease - enzymology; Coronary Artery Disease - genetics; Coronary Artery Disease - pathology; Coronary heart disease; Death, Sudden, Cardiac - etiology; Genetic Predisposition to Disease; Genotype; Heart; Humans; iNOS; Male; Medical sciences; Middle Aged; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; polymorphism; Polymorphism, Genetic; Prospective Studies; Risk Factors; Human; Prevalence; Enzyme; Cardiovascular disease; Synthase; Gene expression; Coronary heart disease; Coronary artery disease; Gases; Autopsy; Nitric oxide; iNOS; Diagnosis; Cadaver; Polymorphism
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/j.1365-2362.2003.01271.x

Background  Recent studies using reporter gene constructs have indicated significant differences in the promoter activity of inducible nitric oxide synthase (iNOS) gene variants. Although the exact role of iNOS in atherogenesis is unclear, it is possible that this variation site may influence the extent of coronary artery disease (CAD). Methods  We amplified these (AAAT) repeat variants from the NOS2A gene (denoted iNOS R4 and iNOS R5) from 325 Finnish men included in the Helsinki Sudden Death Study, and studied their association with indices of stenosis and atherosclerosis of the left anterior descending artery (LAD), right coronary artery (RCA) and left circumflex artery (LCX). In order to understand the effect of iNOS genotype on different stages of CAD, our study population was divided into age groups. Results  In the LAD, the progression of atherosclerosis seemed to be more pronounced in the 4/5 genotype carriers than in those with the 4/4 genotype when the different age groups were compared. More specifically, statistically significant differences between the genotypes were found in the subgroup of men aged > 55 years. In this group, men carrying the rare R4/5 genotype presented higher mean values of stenosis percentages (55% vs. 42%, P = 0·008), larger areas of fatty streaks (10·4% vs. 5·9%; P = 0·01) and complicated lesions (3·5% vs. 1·3%; P = 0·001) compared with the R4/4 carriers. No significant association of iNOS genotypes with stenosis and atherosclerosis of RCA and LCX was found. Conclusions  It appears unlikely the R4/5 genotype plays a major role in the pathogenesis of CAD, as it was not associated with stenosis and atherosclerosis in RCA and LCX. However this genotype may have some role in more pronounced CAD, as seen in the LAD.