Influence of Polymorphisms in the RANKL/RANK/OPG Signaling Pathway on Volumetric Bone Mineral Density and Bone Geometry at the Forearm in Men

Delnaz Roshandel, Kate L. Holliday, Stephen R. Pye, Kate A. Ward, Steven Boonen, Dirk Vanderschueren, Herman Borghs, Ilpo T. Huhtaniemi, Judith E. Adams, Gyorgy Bartfai, Felipe F. Casanueva, Joseph D. Finn, Gianni Forti, Aleksander Giwercman, Thang S. Han, Krzysztof Kula, Michael E. Lean, Neil Pendleton, Margus Punab, Alan J. SilmanFrederick C. Wu, Wendy Thomson, Terence W. O'Neill

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Abstract

We sought to determine the influence of single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG on volumetric bone mineral density (vBMD) and bone geometry at the radius in men. Pairwise tag SNPs (r 2 ≥ 0.8) for RANKL (n = 8), RANK (n = 44), and OPG (n = 22) and five SNPs near RANKL and OPG strongly associated with areal BMD in genomewide association studies were previously genotyped in men aged 40-79 years in the European Male Ageing Study (EMAS). Here, these SNPs were analyzed in a subsample of men (n = 589) who had peripheral quantitative computed tomography (pQCT) performed at the distal (4%) and mid-shaft (50%) radius. Estimated parameters were total and trabecular vBMD (mg/mm 3) and cross-sectional area (mm 2) at the 4% site and cortical vBMD (mg/mm 3); total, cortical, and medullary area (mm 2); cortical thickness (mm); and stress strain index (SSI) (mm 3) at the 50% site. We identified 12 OPG SNPs associated with vBMD and/or geometric parameters, including rs10505348 associated with total vBMD (β [95% CI] = 9.35 [2.12-16.58], P = 0.011), cortical vBMD (β [95% CI] = 5.62 [2.10-9.14], P = 0.002), cortical thickness (β [95% CI] = 0.08 [0.03-0.13], P = 0.002), and medullary area (β [95% CI] = -2.90 [-4.94 to -0.86], P = 0.005) and rs2073618 associated with cortical vBMD (β [95% CI] = -4.30 [-7.78 to -0.82], P = 0.015) and cortical thickness (β [95% CI] = -0.08 [-0.13 to -0.03], P = 0.001). Three RANK SNPs were associated with vBMD, including rs12956925 associated with trabecular vBMD (β [95% CI] = -7.58 [-14.01 to -1.15], P = 0.021). There were five RANK SNPs associated with geometric parameters, including rs8083511 associated with distal radius cross-sectional area (β [95% CI] = 8.90 [0.92-16.88], P = 0.029). No significant association was observed between RANKL SNPs and pQCT parameters. Our findings suggest that genetic variation in OPG and RANK influences radius vBMD and geometry in men.

Original languageEnglish
Pages (from-to)446-455
Number of pages10
JournalCalcified Tissue International
Volume89
Issue number6
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Genetic association
  • Genetic polymorphism
  • Male
  • Osteoporosis
  • QCT

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine
  • Endocrinology

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    Roshandel, D., Holliday, K. L., Pye, S. R., Ward, K. A., Boonen, S., Vanderschueren, D., Borghs, H., Huhtaniemi, I. T., Adams, J. E., Bartfai, G., Casanueva, F. F., Finn, J. D., Forti, G., Giwercman, A., Han, T. S., Kula, K., Lean, M. E., Pendleton, N., Punab, M., ... O'Neill, T. W. (2011). Influence of Polymorphisms in the RANKL/RANK/OPG Signaling Pathway on Volumetric Bone Mineral Density and Bone Geometry at the Forearm in Men. Calcified Tissue International, 89(6), 446-455. https://doi.org/10.1007/s00223-011-9532-y