Context: Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator nuclear factor κ-β that blocks osteoclastic bone resorption. Objective: We investigated the association between a Lys3Asn polymorphism in the OPG gene and bone mineral density (BMD), and the risk of fracture in 6695 women aged 65 yr and older participating in the Study of Osteoporotic Fractures. Design: BMD was measured using either single-photon absorptiometry (Osteon Osteoanalyzer; Dove Medical Group, Los Angeles, CA) or dual-energy x-ray absorptiometry (Hologic QDR 1000; Hologic, Inc., Bedford, MA). Incident fractures were confirmed by physician adjudication of radiology reports. Genotyping was performed using an immobilized probe-based assay. Results: Women who were homozygous for the minor G (Lys) allele had significantly lower BMD at the intertrochanter, distal radius, lumbar spine, and calcaneus than those with the C (Asn) allele. There were 701 incident hip fractures during 13.6-yr follow-up (91,249 person-years), including 362 femoral neck and 333 intertrochanteric hip fractures.Womenwith the C/C (Asn-Asn) genotype had a 51% higher risk of femoral neck fracture (95% confidence interval, 1.13-2.02) and 26% higher risk of hip fracture(95%confidence interval, 1.02-1.54) than those with the G/G (Lys-Lys) genotype. These associations were independent of BMD. Intertrochanteric fractures were not associated with the Lys3Asn polymorphism. Conclusion: These results require confirmation but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women.
Bibliographical noteFunding Information:
Disclosure Summary: J.A.C. receives funding from Merck Co., Eli Lily Co., Pfizer Pharmaceuticals, and Novartis Pharmaceuticals. K.E.E. is a federal employee of the Veterans Affairs Medical Center in Minneapolis, MN, and has received research support from California Pacific Medical Center, which receives funding from Roche Molecular Systems. M.C.H. acts as a consultant for Amgen, Inc. J.L., S.C., and J.M.L. are all employees of Roche Molecular Systems, which provided genotyping reagents and services for this study at no cost under a research collaboration. G.P. is an employee of Roche Palo Alto. S.R.C. is an employee of the California Pacific Medical Center and receives research support from Roche Molecular Systems. All other authors have no conflicts of interest.
This study was supported by Public Health Service Grants AG05407, AR35582, AG05394, AR35584, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, and 2 R01 AG027574-22A1. J.I.O. and S.P.M. were supported by National Institute on Aging Grant T32 AG00181-13.