Published Online
on April 8, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on November 27, 2003
Revised on January 23, 2004
Accepted on February 10, 2004

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; and 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.

^* To whom correspondence should be addressed. 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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