Subscribe to RSS
DOI: 10.1055/s-2003-37494
J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York
Endothelial Nitric Oxide Synthase (ecNOS) 4 a/b Gene Polymorphism and Carotid Artery Intima-Media Thickness in Type-1 Diabetic Patients
Publication History
Received: April 11, 2002
First decision: June 26, 2002
Accepted: September 8, 2002
Publication Date:
26 February 2003 (online)

Abstract
Aim
To study putative associations of the ecNOS 4 a/b polymorphism with carotid artery intima-media thickness (IMT) and diabetic complications in young type-1 diabetic patients.
Methods
Study participants were 147 type-1 diabetic patients (56 men and 91 women), mean age 30.1 ± 6.6 years (range 14 - 44), with a diabetes duration of 13.1 ± 8.1 years. HbA1c, albuminuria, and lipid status were assessed by standard laboratory techniques, the ecNOS 4 a/b genotype was determined by polymerase chain reaction with subsequent polyacrylamide gel electrophoresis. The patients were categorized according to the presence or absence of hypertension, nephropathy and retinopathy. The IMT, which can be used to estimate early stages of arteriosclerosis, was measured by high-resolution ultrasonography.
Results
The ecNOS genotypes were distributed as follows: 7.5 % a/a, 30.6 % a/b, and 61.9 % b/b. The IMT values did not differ between the patients with various ecNOS genotypes (a/a: 0.62 ± 0.13; a/b: 0.63 ± 0.21; b/b: 0.63 ± 0.13; all: 0.63 ± 0.15 mm). The prevalence of retinopathy was significantly higher in patients with the b/b genotype (odds ratio: 2.4 vs. a/a+a/b; 95 % CI, 1.1 - 5.3).
Conclusions
Our results do not support the hypothesis that the ecNOS 4 a/b polymorphism interacts with the development of early carotid arteriosclerosis in young type-1 diabetic patients, but they give grounds to assume that in these patients it could influence the occurence of diabetic retinopathy.
Key words
Endothelial nitric oxide - Type 1 diabetes mellitus - Carotid artery - Intima-media thickness - Retinopathy
References
- 1 Bonnardeaux A, Nadaud S, Charru A, Jeunemaitre X, Corvol P, Soubrier F. Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension. Circulation. 1995; 91 96-102
- 2 Chan N N, Vallance P, Colhoun H M. Nitric oxide and vascular responses in Type 1 diabetes. Diabetologia. 2000; 43 137-147
- 3 Cine N, Hatemi A C, Erginel-Unaltuna N. Association of a polymorphism of the ecNOS gene with myocardial infarction in a subgroup of Turkish MI patients. Clin Genet. 2002; 61 66-70
- 4 Förstermann U, Closs E I, Pollock J S, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isozymes. Charcterization, purification, molecular cloning, and functions. Hypertension. 1994; 23 1121-1131
- 5 Frost D, Beischer W. Determinants of carotid artery wall thickening in young patients with type 1 diabetes mellitus. Diabet Med. 1998; 15 851-857
- 6 Frost D, Pfohl M, Clemens P, Häring H J, Beischer W. Evaluation of the insertion/deletion ACE gene polymorphism as a risk factor for carotid artery intima-media thickening and hypertension in young type 1 diabetic patients. Diabet Care. 1998 a; 21 836-840
- 7 Frost D, Friedl A, Beischer W. Bestimmung der Intima-Media-Dicke an der Arteria carotis: methoden-, probanden- und untersucherabhängige Einflüsse. Ultraschall in Med. 1998 b; 19 168-173
- 8 Frost D, Friedl A, Beischer W. Determinants of early carotid atherosclerosis progression in young patients with type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2002; 110 92-94
- 9 Fujita H, Narita T, Meguro H, Ishii T, Hanyu O, Suzuki K, Kamoi K, Ito S. Lack of association between an ecNOS gene polymorphism and diabetic nephropathy in type 2 diabetic patients with proliferative diabetic retinopathy. Horm Metab Res. 2000; 32 80-83
- 10 Gardemann A, Lohre J, Cayci S, Katz N, Tillmanns H, Haberbosch W. The T allele of the missense Glu(298)Asp endothelial nitric oxide synthase gene polymorphism is associated with coronary heart disease in younger individuals with high atherosclerotic risk profile. Atherosclerosis. 2002; 160 167-175
- 11 Grobbee D E, Bots M L. Carotid artery intima-media thickness as an indicator of generalized atherosclerosis. J Intern Med. 1994; 236 567-573
- 12 Hattenbach L O, Allers A, Klais C, Koch F, Hecker M. L-Arginine-nitric oxide pathway related metabolites in the aqueous humor of diabetic patients. Invest Ophthalmol Vis Sci. 2000; 41 213-217
- 13 Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, Ochiai H, Kosuge M, Watanabe Y, Yoshii Y, Kihara M, Kimura K, Ishii M, Umemura S. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension. 1998; 32 521-526
- 14 Kuboki K, Jiang Z Y, Takahara N, Ha S W, Igarashi M, Yamauchi T, Feener E P, Herbert T P, Rhodes C J, King G L. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo. A specific vascular action of insulin. Circulation. 2000; 101 676-681
- 15 Nakagami H, Ikeda U, Maeda Y, Yamamoto K, Hojo Y, Kario K, Kuroki S, Shimada K. Coronary artery disease and endothelial nitric oxide synthase and angiotensin-converting enzyme gene polymorphisms. Thromb Thrombolysis. 1999; 8 191-195
- 16 Neugebauer S, Baba T, Watanabe T. Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes. Diabetes. 2000; 49 500-503
- 17 Roth S. Role of nitric oxide in retinal cell death. Clin Neurosci. 1997; 4 216-223
- 18 Salonen R, Salonen J T. Determinants of carotid intima-media thickness: a population-based ultrasonography study in Eastern Finnish men. J Intern Med. 1991; 229 225-231
- 19 Salonen R, Haapanen A, Salonen J. Measurement of intima-media thickness of common carotid arteries with high-resolution B-mode ultrasonography: inter- and intra-observer variability. Ultrasound Med Biol. 1991; 17 225-230
- 20 Salonen J T, Salonen R. Ultrasound B-Mode imaging in observational studies of atherosclerotic progression. Circulation. 1993; 87 (Suppl 2) II 56-II 65
- 21 Schmetterer L, Findl O, Fasching P, Ferber W, Strenn K, Breiteneder H, Adam H, Eichler H G, Wolzt M. Nitric oxide and ocular blood flow in patients with IDDM. Diabetes. 1997; 46 653-658
- 22 Sigusch H H, Surber R, Lehmann M H, Surber S, Weber J, Henke A, Reinhardt D, Hoffmann A, Figulla H R. Lack of association between 27-bp repeat polymorphism in intron 4 of the endothelial nitric oxide synthase gene and the risk of coronary artery disease. Scand J Clin Lab Invest. 2000; 60 229-235
- 23 Taniwaki H, Ishimura E, Matsumoto N, Emoto M, Inaba M, Nishizawa Y. Relations between ACE gene and ecNOS gene polymorphism and resistive index in type 2 diabetic patients with nephropathy. Diabet Care. 2001; 24 1653-1660
- 24 Traub O, van Bibber R. Role of nitric oxide in insulin-dependent diabetes mellitus-related vascular complications. West J Med. 1995; 162 439-445
- 25 Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A, Kawaguchi Y, Hosoya T, Igari J. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun. 1998; 245 190-193
- 26 Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production. Key role of L-arginine availability. Circulation. 2000; 101 1261-1266
- 27 Wang X L, Sim A S, Badenhop R F, McCredie R M, Wilcken D EL. A smoking-dependent risk for coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nature Medicine. 1996; 2 41-45
- 28 Wendelhag I, Gustavsson T, Suurküla M, Wikstrand J. Ultrasound measurement of wall thickness in the carotid artery: fundamental principles and description of a computerized analysing system. Clin Physiol. 1991; 11 565-577
- 29 WHO Expert Committee on Diabetes Mellitus .World Health Organisation Technical Report Series 640. Geneva; 1980
- 30 Wikstrand J, Wendelhag I. Methodological considerations of ultrasound investigation of intima-media thickness and lumen diameter. J Intern Med. 1994; 236 555-559
Dr. med. Dietmar Frost
Krankenhaus Waldfriede · Innere Abteilung
Argentinische Allee 40
14163 Berlin
Germany
Phone: 030/81810243
Fax: 030/81810111
Email: d.frost@waldfriede.de