Endothelial nitric oxide synthase Glu(298)-->Asp polymorphism, carotid atherosclerosis and intima-media thickness in a general population sample.

The Glu 298 → Asp (E298D; 894G → T) polymorphism of eNOS (endothelial nitric oxide synthase) has been related with cardiovascular disease. In the present study, we investigated the association of Glu 298 → Asp with atherosclerotic plaques in different carotid vessel segments and with carotid IMT (intima-media thickness). The Glu 298 → Asp eNOS polymorphism was determined by 5 � -exonuclease assay among 2448 participants of the SHIP (Study of Health in Pomerania). Mean and maximum common carotid IMT, as well as carotid atherosclerosis, were measured by high-resolution ultrasound. The Asp/Asp 298 genotype was associated with an increased risk of atherosclerotic plaques at the level of the common carotid arteries [multivariate odds ratio, 1.57 and 95 % CI (confidence interval), 1.05–2.34; P = 0.025], but not in the carotid bifurcations or internal or external carotid arteries. Glu 298 → Asp genotype was not associated with carotid IMT in the whole sample. However, the Asp/Asp 298 genotype was independently associated with both higher mean [adjusted increase by 0.046 mm (95 % CI, 0.013–0.078); P = 0.006] and maximum carotid IMT [0.137 mm (95 % CI, 0.064–0.209); P < 0.001] in the low-risk group of subjects without carotid atherosclerosis. In conclusion, the Asp/Asp 298 genotype is associated with atherosclerosis in the common carotid arteries and, in a low-risk group, also with carotid IMT. This suggests that the association of the Glu 298 → Asp genotype with atherosclerosis in the carotid arteries is site-specific and is modified by overall cardiovascular risk.

[1]  S. Kiechl,et al.  Distinct risk profiles of early and advanced atherosclerosis: prospective results from the Bruneck Study. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[2]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[3]  P. Tsao,et al.  Regression or progression. Dependency on vascular nitric oxide. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[4]  G. Remuzzi,et al.  Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. , 1995, Circulation research.

[5]  R. Kronmal,et al.  Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. , 1999, The New England journal of medicine.

[6]  A. Hassid,et al.  Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. , 1989, The Journal of clinical investigation.

[7]  M. Lathrop,et al.  Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene. , 1994, Biochemical and biophysical research communications.

[8]  B. Mayer,et al.  Functional characterization of Glu298Asp mutant human endothelial nitric oxide synthase purified from a yeast expression system. , 2003, Nitric oxide : biology and chemistry.

[9]  J. Umans,et al.  Nitric oxide in the regulation of blood flow and arterial pressure. , 1995, Annual review of physiology.

[10]  K. Channon,et al.  Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. , 1999, Circulation.

[11]  G D Lowe,et al.  Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. , 1999, Stroke.

[12]  J. Bauer,et al.  Therapeutic implications of human endothelial nitric oxide synthase gene polymorphism. , 2001, Trends in pharmacological sciences.

[13]  B. Trimarco,et al.  A Common Variant of Endothelial Nitric Oxide Synthase (Glu298Asp) Is an Independent Risk Factor for Carotid Atherosclerosis , 2001, Stroke.

[14]  P. Doevendans,et al.  The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide , 2002, Journal of hypertension.

[15]  W Riley,et al.  Risk factors and segment-specific carotid arterial enlargement in the Atherosclerosis Risk in Communities (ARIC) cohort. , 1996, Stroke.

[16]  S. Alper,et al.  Hemodynamic shear stress and its role in atherosclerosis. , 1999, JAMA.

[17]  U. Paradossi,et al.  Endothelial Function and Carotid Intima-Media Thickness in Young Healthy Subjects Among Endothelial Nitric Oxide Synthase Glu298→Asp and T−786→C Polymorphisms , 2004, Stroke.

[18]  J. Moss,et al.  Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Ross,et al.  The pathogenesis of atherosclerosis (first of two parts). , 1976, The New England journal of medicine.

[20]  M. Bond,et al.  Site-Specific Atherosclerotic Plaques in the Carotid Arteries of Middle-Aged Women From Southern Italy: Associations With Traditional Risk Factors and Oxidation Markers , 2001, Stroke.

[21]  T. Cole,et al.  Glu298Asp Endothelial Nitric Oxide Synthase Gene Polymorphism Interacts With Environmental and Dietary Factors to Influence Endothelial Function , 2000, Circulation research.

[22]  U. John,et al.  Association Between High Serum Ferritin Levels and Carotid Atherosclerosis in the Study of Health in Pomerania (SHIP) , 2004, Stroke.

[23]  S. Scherer,et al.  Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. , 1993, The Journal of biological chemistry.

[24]  R. D. Rudic,et al.  Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. , 1998, The Journal of clinical investigation.

[25]  M. Motomiya,et al.  Flow Patterns in the Human Carotid Artery Bifurcation , 1984, Stroke.

[26]  R. Nerem,et al.  Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. , 1996, Circulation research.

[27]  A. Hingorani,et al.  A Common Variant in Exon 7 of the Endothelial Constitutive Nitric Oxide Synthase Gene: Identification by Single Strand Conformation Polymorphism Analysis , 1995 .

[28]  A. Hingorani,et al.  A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. , 1999, Circulation.

[29]  M. Laule,et al.  High CA repeat numbers in intron 13 of the endothelial nitric oxide synthase gene and increased risk of coronary artery disease. , 2000, Pharmacogenetics.

[30]  O. Joakimsen,et al.  Sex differences in the relationship of risk factors to subclinical carotid atherosclerosis measured 15 years later : the Tromsø study. , 2000, Stroke.

[31]  S. Umemura,et al.  Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. , 1998, Hypertension.

[32]  M. Hennerici,et al.  STROKE RISK FROM SYMPTOMLESS EXTRACRANIAL ARTERIAL DISEASE , 1982, The Lancet.

[33]  K. Tokunaga,et al.  Association of eNOS Glu298Asp Polymorphism With End-Stage Renal Disease , 2002, Hypertension.