Genetic Contribution of the Endothelial Constitutive Nitric Oxide Synthase Gene to Plasma Nitric Oxide Levels

Abstract

Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.

The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide

“…NO inhibitors upregulate the expression of adhesion molecules and exacerbate several models of inflammation (54,56), including chronic arthritis (57). There is evidence for a strong genetic contribution to the regulation of levels of NO in humans (58), but this is the first study to identify a QTL that regulates these levels. Additionally, the fact that Cia6 regulates arthritis provides a possible mechanistic explanation for its mode of action.…”

Association analysis of endothelial nitric oxide synthase gene polymorphism with primary hypertension in a Singapore population

“…Our finding is comparable with a report that showed significant high levels of NO metabolites among white subjects with 4AA genotype. 26 Furthermore, a study from Korea also elaborated the significant association of 4A allele and plasma NO metabolite concentrations. 27 Moreover, a propensity of high blood urea and creatinine level in hypertensive group in the present study also elucidated lower plasma nitrite level in these subjects.…”

Endothelial NO Synthase Genotype and Risk of Preeclampsia

“…This might account for the increased risk of preeclampsia observed in the present study. Associations between the intron-4 variant and differences in NO pathway activity have also been described, 34 but the data are conflicting. 35 Because this variant is intronic, it is unlikely to be functional in its own right.…”