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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.

Original publication

DOI

10.1002/jbmr.78

Type

Journal article

Journal

J Bone Miner Res

Publication Date

08/2010

Volume

25

Pages

1830 - 1838

Keywords

Absorptiometry, Photon, Adult, Aged, Bone Density, Bone Remodeling, Bone and Bones, Europe, Genetic Association Studies, Genetic Markers, Genetic Variation, Genotype, Humans, Male, Middle Aged, Osteoprotegerin, Polymorphism, Single Nucleotide, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Signal Transduction, Ultrasonography