Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans

K. Cho, S. Demissie, J. Dupuis, L. A. Cupples, S. Kathiresan, T. J. Beck, D. Karasik, D. P. Kiel

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Nitric oxide (NO), produced by endothelial cells, is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOS). NO is known to reduce the ratio of receptor activator of nuclear factor KappaB (RANKL)/osteoprotegerin (OPG), leading to decreased osteoclastogenesis and a reduction in bone resorption. Endothelial nitric oxide synthase (eNOS or NOS3) is the predominant constitutive isoform of nitric NOS within bone. Recently, a NOS3 polymorphism, Glu298Asp, previously implicated in osteoporosis, failed to demonstrate an association with bone mineral density (BMD), although there was some indication of an association with selected geometry indices. Since a single polymorphism does not capture all of the potential variants in a given gene, we investigated a broader coverage of the NOS3 gene with bone density/ultrasound and geometry indices in a sample of unrelated individuals from the Framingham Offspring Study. Our results indicated that the Glu298Asp polymorphism was not associated with BMD but suggested some haplotype-based associations in the linkage disequilibrium (LD) region that included the Glu298Asp polymorphism with several geometry indices. Although our findings exhibited several associations with selected bone density/ultrasound and geometry indices, the nominally significant associations are regarded as primarily hypothesis generating and suggest that replication in other samples is needed. Thus, NOS3 genetic variation does not appear to be a major contributor to adult bone density/ultrasound and geometry in our sample.

Original languageEnglish
Pages (from-to)53-60
Number of pages8
Issue number1
StatePublished - Jan 2008
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), NHLBI's CardioGenomics Program in Genomics Applications ( http://cardiogenomics.med.harvard.edu/home ), the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging (grants No. R01-AR050066 and R01-AR/AG 41398). A portion of this research was conducted using Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the National Center for Research Resources (NIH NCRR) Shared Instrumentation grant (1S10RR163736-01A1).


  • Bone density/ultrasound
  • Bone geometry
  • Genetic polymorphisms
  • Nitric oxide synthase
  • Osteoporosis


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