Lack of Evidence for Linkage of the Endothelial Cell Nitric Oxide Synthase Gene to Essential Hypertension

BACKGROUND: The basal release of nitric oxide by the endothelium plays an important role in regulating blood flow and pressure and mediates most of the endothelium-dependent vasodilation. Impairment of nitric oxide production by specific inhibitors increases blood pressure in humans, and several reports suggest that hypertensive subjects have a blunted endothelium-dependent vasodilatation that might be secondary to decreased nitric oxide production from the vessel wall. METHODS AND RESULTS: To determine whether the endothelial nitric oxide synthase gene is involved in human essential hypertension, we identified informative biallelic and multiallelic markers of this locus and performed case-control and linkage studies in hypertensive subjects and normotensive control subjects. We used the affected sib pair method to test for potential linkage in 145 hypertensive pedigrees (269 sib pairs, 346 subjects) with a highly polymorphic marker of the nitric oxide synthase gene (polymorphism information content of 92%). There was no evidence for linkage among affected siblings. The 95% upper confidence limit of this value suggests that at most 1% of alleles in excess of expected are shared. We also identified two informative biallelic markers of this gene to perform a case-control study on white hypertensive and normotensive subjects. Similar genotype distributions between the two groups were noted for both markers. Estimated haplotype frequencies by maximum likelihood methods combining the two biallelic markers were also similar in both groups. CONCLUSIONS: These findings do not suggest that common molecular variants of the endothelial nitric oxide synthase gene are involved in essential hypertension.