© 1997 American Heart Association, Inc.
Articles |
Genetic Contribution of the Endothelial Constitutive Nitric Oxide Synthase Gene to Plasma Nitric Oxide Levels
From the Department of Cardiovascular Medicine, Prince Henry/Prince of Wales Hospitals (X.L.W., A.S.S., Jun W., R.B.B., D.E.L.W.), and the Department of Medicine, St George Hospital, University of New South Wales (M.C.M., J.B., L.A.), Sydney, Australia; and the Department of Genetics, Southwest Foundation of Biomedical Research, San Antonio, Texas (Jian W.).
Correspondence to Dr X.L. Wang, Department of Cardiovascular Medicine, Clinical Sciences Building, Prince Henry Hospital, Little Bay, NSW 2036, Australia. E-mail x.l.wang{at}unsw.edu.au
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 (
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 µmol/L) were significantly higher
(P=.000242) than those homozygous for the common allele
(30.2±3.1 µmol/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, ie basal NO production. This finding may be
relevant to atherogenesis and NO-related disorders.
Key Words: nitric oxide • endothelial constitutive nitric oxide synthase • DNA polymorphism • quantitative linkage analysis • major locus effect
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