Published online before print April 2, 2007, doi: 10.1161/HYPERTENSIONAHA.106.085266
(Hypertension. 2007;49:1285.)
© 2007 American Heart Association, Inc.
Original Articles |
Vascular Stiffness and Genetic Variation at the Endothelial Nitric Oxide Synthase Locus
The Framingham Heart Study
From Cardiovascular Engineering, Inc (G.F.M., M.V.), Waltham, Mass; National Heart, Lung, and Blood Institute’s Framingham Heart Study (S.K., M.G.L., R.S.V., C.-Y.G., M.J.K., C.N.-C., D.L., C.J.O., E.J.B.), Framingham, Mass; the Department of Mathematics and Statistics (M.J.K., M.G.L.), Evans Department of Medicine and Whitaker Cardiovascular Institute (R.S.V., J.A.V., E.J.B.), Boston University School of Medicine, Boston University, Mass; the Program in Medical and Population Genetics (S.K., C.N.-C., S.L.M., A.L.C., J.A.D., J.N.H.), Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge; the Cardiology Division (S.K., C.N.-C., C.J.O.), Massachusetts General Hospital, Divisions of Genetics and Endocrinology, Children’s Hospital (J.A.D., J.N.H.), and Department of Genetics (J.N.H.), Harvard Medical School, Boston.
Correspondence to Gary F. Mitchell, Cardiovascular Engineering, Inc, 51 Sawyer Rd, Suite 100, Waltham, MA 02453. E-mail GaryFMitchell{at}mindspring.com
Arterial stiffness is a moderately heritable trait that is affected by alterations in the bioavailability of NO. Previous studies have found associations between variants in the gene for endothelial NO synthase (NOS3) and arterial properties. We previously identified a linkage peak for forward pressure wave amplitude in the immediate vicinity of NOS3. Therefore, we evaluated relations between arterial stiffness measures and common genetic variants at this locus. Eighteen single nucleotide polymorphisms capturing 
90% of underlying common variation in NOS3 were genotyped in unrelated Framingham Heart Study participants (N=1157; 52.2% women; mean age: 62 years) with routinely ascertained tonometry data that provided 5 arterial phenotypes (forward and reflected pressure wave amplitude, central pulse pressure, carotid–femoral pulse wave velocity, and mean arterial pressure). In women but not men, the genotype for the common NOS3 missense mutation (Glu298Asp, rs1799983) was related to central pulse pressure (women: GG=53±0.9, GT=54±0.9, and TT=47±2.0 mm Hg, P=0.0047; men: GG=50±1.0, GT=49±0.9, and TT=47±1.8 mm Hg, P=0.30) and forward wave amplitude (women: GG=41±0.7, GT=42±0.7, and TT=38±1.6 mm Hg, P=0.029; men: GG=42±0.9, GT=41±0.8, and TT=39±1.5 mm Hg, P=0.47). The only other nominally significant sex-specific association in men but not women was between an intronic polymorphism (rs1800781) and reflected wave amplitude (women: AA=10.4±0.4, AG=11.1±0.6, and GG=8.9±2.2 mm Hg, P=0.50; men: AA=6.1±0.3, AG=7.3±0.5, and GG=11.3±2.3 mm Hg, P=0.014). After adjusting for multiple testing (18 polymorphisms and 5 phenotypes), these nominal associations were no longer significant. The present study was suggestive of modest relations between common genetic variants at the NOS3 locus and arterial stiffness.
Key Words: single nucleotide polymorphism • nitric oxide synthase • pulse pressure • medical genetics • epidemiology
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