The T(-786)C endothelial nitric oxide synthase genotype predicts cardiovascular mortality in high-risk patients.
OBJECTIVE
This study sought to investigate the impact of a common T(-786)C single-nucleotide polymorphism (SNP) in the promoter of the endothelial nitric oxide synthase (eNOS, NOS3) gene on cardiovascular (CV) death in a prospective cohort study.


BACKGROUND
The T(-786)C SNP eNOS gene implies a blunted endothelium-dependent vasodilation in hypertensive patients and was associated with multivessel coronary artery disease in cross-sectional studies, but it remained unsettled whether it carried prognostic information.


METHODS
In consecutive white patients of the GENICA (Genetic and Environmental Factors in Coronary Atherosclerosis) study, who underwent coronary angiography between 1999 and 2001, we determined the incidence of CV death at follow-up. The eNOS T(-786)C and the exon 7 G(894)T SNPs were determined by melting curve analysis of amplicons from allele-specific fluorescence resonance energy transfer probes. Plasma levels of nitrate/nitrite, nitrotyrosine, and myeloperoxidase were also measured. The Kaplan-Meier and Cox regression analyses were used to assess the impact of SNPs on event-free survival.


RESULTS
Complete follow-up data were obtained in 1,086 (98%) patients. After a median follow-up of 1,296 days (range 4 to 2,057 days), we observed 85 (8.2%) CV deaths. There was a significant impact of the T(-786)C eNOS genotype on CV death-free (p = 0.0102) survival, but no differences in CV death rates across G(894)T genotypes. The TT individuals, who showed a lower survival, exhibited higher plasma myeloperoxidase (p < 0.0001) and lower levels of nitrotyrosine (p < 0.0001) than CC patients.


CONCLUSIONS
The T(-786)C SNP in the promoter of eNOS bears independent prognostic information and is associated with changes in markers of oxidant stress in high-risk white patients referred for coronary angiography.
Rossi
Gian Paolo
GP
DMCS-Internal Medicine 4, University of Padua, Padua, Italy.
Maiolino
Giuseppe
G
Zanchetta
Mario
M
Sticchi
Daniele
D
Pedon
Luigi
L
Cesari
Maurizio
M
Montemurro
Domenico
D
De Toni
Renzo
R
Zavattiero
Silvia
S
Pessina
Achille C
AC
D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000401:mortality*; D002637:Chest Pain / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000201:enzymology / Q000235:genetics*; D003596:Cytosine; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D013941:Thymine
D015415:Biomarkers; D003596:Cytosine; D052250:Nitric Oxide Synthase Type III; D013941:Thymine