Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: An haplotype analysis

Background: Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been associated with the pathogenesis of cardiovascular diseases, but few studies have evaluated the role of eNOS haplotypes on the risk and prognosis of heart failure (HF). This prospective study was designed to analyze the impact of three eNOS polymorphisms (T-786C, VNTR4a/b and Glu298Asp) and their haplotypes on the susceptibility and clinical outcomes in HF outpatients with systolic dysfunction. Methods and results: We conducted a case-control and a cohort study in which 316 HF patients and 360 healthy controls were recruited from a tertiary care university hospital. DNA was extracted from peripheral blood and eNOS polymorphisms were detected by PCR or PCR-RFLP. Patients were predominantly men, had a mean left ventricular ejection fraction of 31% and were followed-up for a median of 41 months; there were 96 deaths, including 58 HF-related deaths. Genotype distribution of the eNOS T-786C, VNTR 4a/b and Glu298Asp was similar between HF patients and controls. Haplotype frequencies differed between HF patients and controls only in African-Brazilians (p = 0.043). African-Brazilian patients that carried the haplotype -786C/4b/Asp298 had a better prognosis than patients that carried other haplotypes (log rank p value = 0.016 for all-cause mortality). In a Cox proportional hazard model adjusted for clinical variables of risk, the -786C/4b/Asp298 haplotype remained as an independent genetic predictor of survival (adjusted HR = 0.11; 95% CI = 0.01-0.83; p = 0.03). Conclusions: The -786C/4b/Asp298 eNOS haplotype had a significant impact on HF susceptibility and prognosis, particularly in African-Brazilian patients. (C) 2012 Elsevier Inc. All rights reserved.