Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.
BACKGROUND
Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited.


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.
Kathiresan
Sekar
S
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA, USA.
Larson
Martin G
MG
Vasan
Ramachandran S
RS
Guo
Chao-Yu
CY
Vita
Joseph A
JA
Mitchell
Gary F
GF
Keyes
Michelle J
MJ
Newton-Cheh
Christopher
C
Musone
Stacy L
SL
Lochner
Amy L
AL
Drake
Jared A
JA
Levy
Daniel
D
O'Donnell
Christopher J
CJ
Hirschhorn
Joel N
JN
Benjamin
Emelia J
EJ
D000368:Aged; D001783:Blood Flow Velocity; D001916:Brachial Artery / Q000502:physiology; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006940:Hyperemia / Q000453:epidemiology / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017678:Sex Distribution; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D014664:Vasodilation / Q000235:genetics*
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III