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CLINICAL RESEARCH

The T^–786C Endothelial Nitric Oxide Synthase Genotype Predicts Cardiovascular Mortality in High-Risk Patients

Gian Paolo Rossi, MD^_*,_*, Giuseppe Maiolino, MD^_*, Mario Zanchetta, MD, Daniele Sticchi, PhD^_*, Luigi Pedon, MD, Maurizio Cesari, MD^_*, Domenico Montemurro, MD^_*, Renzo De Toni, BsD^_*, Silvia Zavattiero, PhD^_* and Achille C. Pessina, MD, PhD^_*

^_* DMCS-Internal Medicine 4
Servizio di Emodinamica and Divisione di Cardiologia Ospedale di Cittadella, University of Padua, Padua, Italy

Manuscript received December 23, 2005; revised manuscript received April 13, 2006, accepted May 2, 2006.

^_* Reprint requests and correspondence: Dr. Gian Paolo Rossi, Clinica Medica 4, University Hospital, via Giustiniani, 2, 35126 Padova, Italy. (Email: gianpaolo.rossi{at}unipd.it).

OBJECTIVES: This study sought to investigate the impact of a common T^–786C 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^–786C 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^–786C and the exon 7 G⁸⁹⁴T 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^–786C eNOS genotype on CV death-free (p = 0.0102) survival, but no differences in CV death rates across G⁸⁹⁴T 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^–786C 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.

Abbreviations and Acronyms   CV = cardiovascular   CAD = coronary artery disease   eNOS = endothelial nitric oxide synthase   HDL = high-density lipoprotein   LDL = low-density lipoprotein   LVEF = left ventricular ejection fraction   MI = myocardial infarction   MMP = matrix metalloproteinase   NO = nitric oxide   RNS = reactive nitrogen species   ROS = reactive oxygen species   SNP = single-nucleotide polymorphism

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