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(Stroke. 2004;35:1305.)
© 2004 American Heart Association, Inc.

Original Contributions

Endothelial Function and Carotid Intima-Media Thickness in Young Healthy Subjects Among Endothelial Nitric Oxide Synthase Glu²⁹⁸Asp and T^–786C Polymorphisms

Umberto Paradossi, MD, FESC; Enrica Ciofini, BiolD; Aldo Clerico, MD; Nicoletta Botto, BiolD, PhD; Andrea Biagini, MD Maria Giovanna Colombo, BiolD

From CNR Institute of Clinical Physiology (U.P., E.C., A.C., N.B., A.B., M.G.C.), G. Pasquinucci Hospital, Massa, Italy; and S. Anna School of University Studies and Doctoral Research (E.C.), University of Pisa, Italy.

Correspondence to Dr Maria Giovanna Colombo, CNR Institute of Clinical Physiology, G. Pasquinucci Hospital, Via Aurelia SUD, 54100 Massa, Italy. E-mail colombo{at}ifc.cnr.it

Background and Purpose— To assess the role of the endothelial nitric oxide synthase (eNOS) gene variants as risk factors for early atherosclerosis, we sought to investigate whether two polymorphisms located in the exon 7 (Glu²⁹⁸Asp) and in the promoter region (T^–786C) of the eNOS gene were associated with functional changes in the endothelium and carotid intima-media thickness (IMT).

Methods— Endothelium-dependent flow-mediated brachial artery dilation (FMD), endothelium-independent dilation response to glyceryl trinitrate (GTN), and carotid IMT were assessed by high-resolution ultrasound in 118 healthy young nonsmoker subjects (30.1±0.5 years) genotyped for the eNOS Glu²⁹⁸Asp and T^–786C polymorphisms.

Results— Carotid IMT was inversely related to FMD by univariate analysis (r=–0.28, P=0.002) and after adjustment for possible confounders in all the subjects (P<0.01). Asp homozygotes had a significantly lower FMD than Glu carriers (Glu/Glu: 15.0%±1.0%, Glu/Asp: 13.3%±0.7%, Asp/Asp: 9.6%±1.6%; P=0.005), whereas FMD was unaffected by the T^–786C variant. Neither the Glu²⁹⁸Asp nor the T^–786C polymorphisms influenced the GTN-mediated dilation. With respect to Glu carriers, Asp/Asp genotype displayed a significantly greater carotid IMT (Glu/Glu: 0.37±0.01 mm, Glu/Asp: 0.35±0.01 mm, Asp/Asp: 0.45±0.03 mm; P=0.0002) and significant correlations between carotid IMT and FMD (r=–0.48, P=0.04) and between carotid IMT and resting brachial artery diameter (r=0.70, P=0.001). No difference in IMT was found across the T^–786C genotypes. By multivariate regression analysis, Asp/Asp genotype was the only significant and independent predictor of flow-mediated brachial artery dilation (FMD) (P=0.04) and carotid intima-media thickness (IMT) (P=0.006).

Conclusions— The eNOS Glu²⁹⁸Asp polymorphism may be related to early atherogenesis.

Key Words: nitric oxide synthase • atherosclerosis • genetics

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