Endothelial nitric oxide synthase haplotypes are associated with features of metabolic syndrome

Background: The metabolic syndrome, a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Endothelium-derived nitric oxide facilitates skeletal muscle glucose uptake, and data from animal models indicate that endothelial nitric oxide synthase (eNOS) gene-null mice present with a phenotype of insulin resistance, hypertension, and hypertriglyceridemia, much like that observed in humans with metabolic syndrome. We used haplotype tagging single nucleotide polymorphisms (htSNPs) to investigate the role of genetic variation in the eNOS gene (NOS3) in metabolic syndrome in humans. Methods: We recruited 738 unrelated persons from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Metabolic syndrome was defined according to the recently modified National Cholesterol Education Program Adult Treatment Panel III guidelines. Results: Haplotype analysis showed a statistically significant association between some NOS3 gene variants and features of metabolic syndrome. Relative to the most common haplotype, 121, the haplotype 212 was associated with an increased odds ratio (OR) for metabolic syndrome [OR = 1.81,95% confidence interval (CI) 1.15-2.84], and for decreased HDL-cholesterol concentrations (OR 1.52, 95% CI 1.01-2.29), and with increased mean values for the homeostasis model assessment of insulin resistance (P = 0.043), and triglycerides (P=0.026). Conclusions: Our results suggest that genetic variation at the eNOS locus is associated with features of metabolic syndrome, and might represent a new genetic susceptibility component for insulin resistance, hypertriglyceridemia, and low HDL-cholesterol concentrations. (c) 2007 American Association for Clinical Chemistry