title: Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men.
abstract: The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r(2) > or = 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMD(a)) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP (beta = 1.83, p = .004) and CTX-I (beta = 17.59, p = 4.74 x 10(-4)), and lower lumbar spine BMD(a) (beta = -0.02, p = .026). The minor allele of rs9594759 (C) was associated with lower PINP (beta = -1.84, p = .003) and CTX-I (beta = -27.02, p = 6.06 x 10(-8)) and higher ultrasound BMD at the calcaneus (beta = 0.01, p = .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men.
authors.affiliation: Arthritis Research UK, Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
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: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Herman
authors.initials: H
authors.lastname: Borghs
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
authors.forename: Judith E
authors.initials: JE
authors.lastname: Adams
authors.forename: Kate A
authors.initials: KA
authors.lastname: Ward
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bartfai
authors.forename: Felipe
authors.initials: F
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: O'Neill
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics*; D001842:Bone and Bones / Q000000981:diagnostic imaging; D005060:Europe; D056726:Genetic Association Studies; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014463:Ultrasonography
chemical_list: D005819:Genetic Markers; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B