Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men |
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| Authors: | Delnaz Roshandel Kate L Holliday Stephen R Pye Steven Boonen Herman Borghs Dirk Vanderschueren Ilpo T Huhtaniemi Judith E Adams Kate A Ward Gyorgy Bartfai Felipe Casanueva Joseph D Finn Gianni Forti Aleksander Giwercman Thang S Han Krzysztof Kula Michael E Lean Neil Pendleton Margus Punab Alan J Silman Frederick C Wu Wendy Thomson Terence W O'Neill and the EMAS Study Group |
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| Affiliation: | 1. Arthritis Research UK, Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom;2. Leuven University Division of Geriatric Medicine, Katholieke Universiteit Leuven, Leuven, Belgium;3. Leuven University Center for Metabolic Bone Diseases, Katholieke Universiteit Leuven, Leuven, Belgium;4. Department of Andrology and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium;5. Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom;6. Clinical Radiology, Imaging Science and Biomedical Engineering, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom;7. MRC‐Human Nutrition Research, Cambridge, United Kingdom;8. Department of Obstetrics, Gynaecology and Andrology, Albert Szent‐Gyorgy Medical University, Szeged, Hungary;9. Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatolog?′a Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain;10. Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy;11. Scanian Andrology Centre, Department of Urology, Malmo University Hospital, University of Lund, Lund, Sweden;12. Department of Human Nutrition, University of Glasgow, Glasgow, Scotland, United Kingdom;13. Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland;14. Clinical Gerontology, The University of Manchester, Manchester Academic Health Science Centre, Hope Hospital, Salford, United Kingdom;15. Andrology Unit, United Laboratories of Tartu University Clinics, Tartu, Estonia;16. Department of Endocrinology, Manchester Royal Infirmary, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom;17. The EMAS Study Group: Florence: Gianni Forti, Luisa Petrone, and Glovanni Corona;18. Leuven: Dirk Vanderschueren, Steven Boonen, and Herman Borghs;19. Lodz: Krzysztof Kula, Jolanta Slowikowska‐Hilczer, and Renata Walczak‐Jedrzejowska;20. London: Ilpo Huhtaniemi;21. Malmo: Aleksander Giwercman;22. Manchester: Frederick Wu, Alan Silman, Terence O'Neill, Joseph Finn, Philip Steer, Abdelouahid Tajar, David Lee, and Stephen Pye;23. Santiago: Felipe Casanueva and Mary Lage;24. Szeged: Gyorgy Bartfai, Imre Fo'ldesi, and Imre Fejes;25. Tartu: Margus Punab and Paul Korrovitz;26. Turku: Min Jiang. |
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| 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 (r2 ≥ 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 (BMDa) 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 (β = 1.83, p = .004) and CTX‐I (β = 17.59, p = 4.74 × 10?4), and lower lumbar spine BMDa (β = ?0.02, p = .026). The minor allele of rs9594759 (C) was associated with lower PINP (β = ?1.84, p = .003) and CTX‐I (β = ?27.02, p = 6.06 × 10?8) and higher ultrasound BMD at the calcaneus (β = 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. © 2010 American Society for Bone and Mineral Research |
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| Keywords: | osteoporosis association SNPs bone turnover markers bone densitometry |
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