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Endothelial Function and Carotid Intima-Media Thickness in Young Healthy Subjects Among Endothelial Nitric Oxide Synthase Glu 298 →Asp and T −786 →C Polymorphisms

2004; Lippincott Williams & Wilkins; Volume: 35; Issue: 6 Linguagem: Inglês

10.1161/01.str.0000126482.86708.37

1524-4628

Umberto Paradossi, Enrica Ciofini, Aldo Clerico, Nicoletta Botto, Andrea Biagini, Maria Giovanna Colombo,

Nitric Oxide and Endothelin Effects

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.