title: Influence of polymorphisms in the RANKL/RANK/OPG signaling pathway on volumetric bone mineral density and bone geometry at the forearm in men.
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.
authors.affiliation: Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Stopford Building, UK. Delnaz.Roshandel@uhn.ca
authors.forename: Delnaz
authors.initials: D
authors.lastname: Roshandel
authors.forename: Kate L
authors.initials: KL
authors.lastname: Holliday
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Pye
authors.forename: Kate A
authors.initials: KA
authors.lastname: Ward
authors.forename: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
authors.forename: Herman
authors.initials: H
authors.lastname: Borghs
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
authors.forename: Judith E
authors.initials: JE
authors.lastname: Adams
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bartfai
authors.forename: Felipe F
authors.initials: FF
authors.lastname: Casanueva
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Finn
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.forename: Aleksander
authors.initials: A
authors.lastname: Giwercman
authors.forename: Thang S
authors.initials: TS
authors.lastname: Han
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kula
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lean
authors.forename: Neil
authors.initials: N
authors.lastname: Pendleton
authors.forename: Margus
authors.initials: M
authors.lastname: Punab
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Silman
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Wu
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Terence W
authors.initials: TW
authors.lastname: ONeill
mesh_terms: D000328:Adult; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000000981:diagnostic imaging*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053245:RANK Ligand / Q000235:genetics*; D011884:Radius / Q000000981:diagnostic imaging; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human