Nitric oxide (NO) is an important bone-signaling molecule. We examined the associations between the Glu298Asp polymorphism of NOS3, indices of bone strength, and the incidence of fracture among 6691 women aged 65 years and older enrolled in the Study of Osteoporotic Fractures. Calcaneal BMD was measured at an initial exam and after an average of 5.9 years of follow-up. Hip BMD was measured at an initial exam and after 3.7 years of follow-up. Baseline spine BMD and hip structural parameters were measured. Incident hip fractures were confirmed by review of radiographic reports; follow-up was greater than 98% complete. Incident vertebral fractures were defined by morphometry using lateral spine radiography at baseline and an average of 3.7 years later. The frequencies of the NOS3 Glu298Asp genotypes were Glu/Glu = 46.2%, Glu/Asp = 42.7%, and Asp/Asp = 11.1%. There were no significant associations between NOS3 genotypes and initial calcaneal BMD, hip BMD, or rate of change in hip or calcaneal BMD. None of the hip structural parameters differed substantially by genotype. NOS3 genotype was not significantly associated with either incident or prevalent radiographic vertebral fractures. Women with the heterozygous Glu/Asp genotype had a borderline statistically significantly lower rate of hip fracture than either the Glu/Glu genotype (HR = 0.87, 95% CI: 0.74, 1.01) or the Asp/Asp genotype (HR = 0.78, 95% CI: 0.62, 0.98). In conclusion, the Glu298Asp polymorphism does not contribute substantially or consistently to indices of bone strength in this sample of older white women, although our findings suggest allelic variation at the NOS3 locus maybe associated with hip fracture risk. Confirmation of these findings is needed in other populations and with additional markers within and flanking the NOS3 gene region.
Bibliographical noteFunding Information:
This study was supported by grants from the National Institutes of Health through the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants AG05407, AR35582, AG05394, AR35584, and AR35583). BCT was supported with funding from the Veterans Health Administration Office of Health Services Research and Development. Genotyping was done by Roche Molecular Systems in Alameda, California. The authors acknowledge the genotype strip development support of Sheila Cayabyab. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.
- Bone density
- Candidate genes
- Nitric oxide synthase