Endothelial function and carotid intima-media thickness in young healthy subjects among endothelial nitric oxide synthase Glu298→Asp and T-786→C polymorphisms

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 (Glu(298)-->Asp) and in the promoter region (T-786-->C) 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 Glu(298)-->Asp and T-786-->C 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-786 -> C variant. Neither the Glu(298)-> Asp nor the T-786 -> C 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-786-->C 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 Glu(298)-->Asp polymorphism may be related to early atherogenesis.