Endothelial function and carotid intima-media thickness in young healthy subjects among endothelial nitric oxide synthase Glu298-->Asp and T-786-->C polymorphisms.
OBJECTIVE
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 (Glu298-->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 Glu298-->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 Glu298-->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 Glu298-->Asp polymorphism may be related to early atherogenesis.
Paradossi
Umberto
U
CNR Institute of Clinical Physiology, G. Pasquinucci Hospital, Massa, Italy.
Ciofini
Enrica
E
Clerico
Aldo
A
Botto
Nicoletta
N
Biagini
Andrea
A
Colombo
Maria Giovanna
MG
D000328:Adult; D019943:Amino Acid Substitution; D001161:Arteriosclerosis / Q000235:genetics; D001916:Brachial Artery / Q000502:physiology; D002339:Carotid Arteries / Q000033:anatomy & histology* / Q000000981:diagnostic imaging; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D011110:Polymorphism, Genetic; D017539:Tunica Intima / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D017540:Tunica Media / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D014463:Ultrasonography
C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III