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(Circulation. 2005;112:1419-1427.)
© 2005 American Heart Association, Inc.

Epidemiology

Common Genetic Variation at the Endothelial Nitric Oxide Synthase Locus and Relations to Brachial Artery Vasodilator Function in the Community

Sekar Kathiresan, MD; Martin G. Larson, ScD; Ramachandran S. Vasan, MD; Chao-Yu Guo, PhD; Joseph A. Vita, MD; Gary F. Mitchell, MD; Michelle J. Keyes, MS; Christopher Newton-Cheh, MD, MPH; Stacy L. Musone, BA; Amy L. Lochner, BA; Jared A. Drake, BA; Daniel Levy, MD; Christopher J. O’Donnell, MD, MPH; Joel N. Hirschhorn, MD, PhD; Emelia J. Benjamin, MD, ScM

From the Framingham Heart Study of the National Heart, Lung, and Blood Institute (S.K., M.G.L., R.S.V., C.G., M.J.K., C.N.-C., D.L., C.J.O., E.J.B.), Framingham, Mass; Department of Mathematics and Statistics (M.G.L.), Evans Department of Medicine (R.S.V., J.A.V., E.J.B.), and Whitaker Cardiovascular Institute (R.S.V., J.A.V., E.J.B.), Boston University, Boston, Mass; Cardiovascular Engineering, Inc, Waltham, Mass (G.F.M.); Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Mass (S.K., C.N.-C., S.L.M., A.L.L., J.A.D., C.J.O., J.N.H.); and 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, Mass.

Correspondence to Emelia J. Benjamin, MD, ScM, Department of Medicine, Boston University School of Medicine, Framingham Heart Study, 73 Mt Wayte Ave, Suite 2, Framingham, MA 01702-5827. E-mail emelia{at}bu.edu

Received February 21, 2005; revision received May 25, 2005; accepted June 14, 2005.

Background— Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited.

Methods and Results— In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.5% women; mean age, 62 years) with measured brachial artery flow-mediated dilation (n=1446) or hyperemic flow velocity (n=1043). Within 3 defined blocks of strong linkage disequilibrium that spanned NOS3, 11 SNPs captured >80% of common haplotypic variation. Among men, there were nominally significant associations between 8 NOS3 SNPs (minimum P=0.002) and between haplotypes (minimum P=0.002) and either flow-mediated dilation or hyperemic flow velocity. In women, we did not observe significant associations between NOS3 SNPs or haplotypes and endothelial function measures. To correct for multiple testing, we constructed 1000 bootstrapped null data sets and found that empirical probability values exceeded 0.05 for both phenotypes.

Conclusions— A parsimonious set of SNPs captures common genetic variation at the NOS3 locus. A conservative interpretation of our results is that, accounting for multiple testing, we did not observe statistically significant relations between NOS3 sequence variants and endothelial function measures in either sex. The nominal associations of select NOS3 variants with endothelial function in men (unadjusted for multiple testing) should be viewed as hypothesis-generating observations and may merit testing in other cohorts and experimental designs.

Key Words: endothelium • epidemiology • genetics • nitric oxide synthase

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