Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men.
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.
Roshandel
Delnaz
D
Arthritis Research UK, Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Holliday
Kate L
KL
Pye
Stephen R
SR
Boonen
Steven
S
Borghs
Herman
H
Vanderschueren
Dirk
D
Huhtaniemi
Ilpo T
IT
Adams
Judith E
JE
Ward
Kate A
KA
Bartfai
Gyorgy
G
Casanueva
Felipe
F
Finn
Joseph D
JD
Forti
Gianni
G
Giwercman
Aleksander
A
Han
Thang S
TS
Kula
Krzysztof
K
Lean
Michael E
ME
Pendleton
Neil
N
Punab
Margus
M
Silman
Alan J
AJ
Wu
Frederick C
FC
Thomson
Wendy
W
O'Neill
Terence W
TW
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
D005819:Genetic Markers; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B