Human Genetics

, Volume 118, Issue 5, pp 568–577

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men

Authors

  • Yi-Hsiang Hsu
    • Program for Population GeneticsHarvard School of Public Health
  • Tianhua Niu
    • Division of Preventive Medicine, Department of MedicineBrigham and Women Hospital, Harvard Medical School
  • Henry A. Terwedow
    • Program for Population GeneticsHarvard School of Public Health
  • Xin Xu
    • Program for Population GeneticsHarvard School of Public Health
  • Yan Feng
    • Program for Population GeneticsHarvard School of Public Health
  • Zhiping Li
    • Institute of MedicineAnhui Medical University
  • Joseph D. Brain
    • Program for Population GeneticsHarvard School of Public Health
  • Cliff J. Rosen
    • Maine Center for Osteoporosis Research and EducationSt. Joseph Hospital
  • Nan Laird
    • Department of BiostatisticsHarvard School of Public Health
    • Program for Population GeneticsHarvard School of Public Health
    • Institute of MedicineAnhui Medical University
Original Investigations

DOI: 10.1007/s00439-005-0062-4

Cite this article as:
Hsu, Y., Niu, T., Terwedow, H.A. et al. Hum Genet (2006) 118: 568. doi:10.1007/s00439-005-0062-4

Abstract

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5′ UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P=0.004), and lower whole body BMD (P<0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P<0.01), and higher whole body BMD (P<0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P<0.05), and higher whole body BMD (P<0.01). Significant gene–gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.

Supplementary material

439_2005_62_MOESM1_ESM.pdf (132 kb)
Supplementary material

Copyright information

© Springer-Verlag 2005