This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ralston, S. H. Search for Related Content PubMed PubMed Citation Articles by Ralston, S. H.

Genetic Control of Susceptibility to Osteoporosis

Department of Medicine and Therapeutics, University of Aberdeen Medical School, Aberdeen, AB25 2ZD, United Kingdom

Address all correspondence and requests for reprints to: Stuart H. Ralston, M.D., Professor of Medicine and Bone Metabolism, University of Aberdeen Medical School, Department of Medicine and Therapeutics, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail: . s.ralston{at}abdn.ac.uk

Abstract

Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33–35, 6p11–12, and 11q12–13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism affecting an Sp1 binding site has been identified in the collagen type I 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality.

An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease.

This article has been cited by other articles:

				F. F. Bezerra, G. M. K. Cabello, L. M. C. Mendonca, and C. M. Donangelo Bone Mass and Breast Milk Calcium Concentration Are Associated with Vitamin D Receptor Gene Polymorphisms in Adolescent Mothers J. Nutr., February 1, 2008; 138(2): 277 - 281. [Abstract] [Full Text] [PDF]

				L. S. H. Nissen-Meyer, R. Jemtland, V. T. Gautvik, M. E. Pedersen, R. Paro, D. Fortunati, D. D. Pierroz, V. A. Stadelmann, S. Reppe, F. P. Reinholt, et al. Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice J. Cell Sci., August 15, 2007; 120(16): 2785 - 2795. [Abstract] [Full Text] [PDF]

				B. Edderkaoui, D. J. Baylink, W. G. Beamer, J. E. Wergedal, R. Porte, A. Chaudhuri, and S. Mohan Identification of mouse Duffy Antigen Receptor for Chemokines (Darc) as a BMD QTL gene Genome Res., May 1, 2007; 17(5): 577 - 585. [Abstract] [Full Text] [PDF]

				J. A. Riancho, C. Valero, A. Naranjo, D. J. Morales, C. Sanudo, and M. T. Zarrabeitia Identification of an Aromatase Haplotype That Is Associated with Gene Expression and Postmenopausal Osteoporosis J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 660 - 665. [Abstract] [Full Text] [PDF]

				M. T Zarrabeitia, J. L Hernandez, C. Valero, A. Zarrabeitia, J. A Amado, J. Gonzalez-Macias, and J. A Riancho Adiposity, estradiol, and genetic variants of steroid-metabolizing enzymes as determinants of bone mineral density Eur. J. Endocrinol., January 1, 2007; 156(1): 117 - 122. [Abstract] [Full Text] [PDF]

				J. A Riancho, M. T Zarrabeitia, C. Valero, C. Sanudo, V. Mijares, and J. Gonzalez-Macias A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density. Eur. J. Endocrinol., July 1, 2006; 155(1): 53 - 59. [Abstract] [Full Text] [PDF]

				U.H. Lerner Inflammation-induced Bone Remodeling in Periodontal Disease and the Influence of Post-menopausal Osteoporosis. J. Dent. Res., July 1, 2006; 85(7): 596 - 607. [Abstract] [Full Text] [PDF]

				D. T. Fritz, S. Jiang, J. Xu, and M. B. Rogers A Polymorphism in a Conserved Posttranscriptional Regulatory Motif Alters Bone Morphogenetic Protein 2 (BMP2) RNA:Protein Interactions Mol. Endocrinol., July 1, 2006; 20(7): 1574 - 1586. [Abstract] [Full Text] [PDF]

				M. Rao Vupputuri, R. Goswami, N. Gupta, D. Ray, N. Tandon, and N. Kumar Prevalence and functional significance of 25-hydroxyvitamin D deficiency and vitamin D receptor gene polymorphisms in Asian Indians Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1411 - 1419. [Abstract] [Full Text] [PDF]

				A. J. Sanchez and J. Aranda-Michel Liver Disease and Osteoporosis Nutr Clin Pract, June 1, 2006; 21(3): 273 - 278. [Abstract] [Full Text] [PDF]

				Y. Ikeda, M. Iki, A. Morita, E. Kajita, S. Kagamimori, Y. Kagawa, and H. Yoneshima Intake of Fermented Soybeans, Natto, Is Associated with Reduced Bone Loss in Postmenopausal Women: Japanese Population-Based Osteoporosis (JPOS) Study J. Nutr., May 1, 2006; 136(5): 1323 - 1328. [Abstract] [Full Text] [PDF]

				Y.-T. Sheu, J. M. Zmuda, J. A. Cauley, S. P. Moffett, C. J. Rosen, C. Ishwad, and R. E. Ferrell Nuclear Receptor Coactivator-3 Alleles Are Associated with Serum Bioavailable Testosterone, Insulin-Like Growth Factor-1, and Vertebral Bone Mass in Men J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 307 - 312. [Abstract] [Full Text] [PDF]

				T. V. Nguyen, L. M. Esteban, C. P. White, S. F. Grant, J. R. Center, E. M. Gardiner, and J. A. Eisman Contribution of the Collagen I {alpha}1 and Vitamin D Receptor Genes to the Risk of Hip Fracture in Elderly Women J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6575 - 6579. [Abstract] [Full Text] [PDF]

				K. Michaelsson, H. Melhus, H. Ferm, A. Ahlbom, and N. L. Pedersen Genetic Liability to Fractures in the Elderly Arch Intern Med, September 12, 2005; 165(16): 1825 - 1830. [Abstract] [Full Text] [PDF]

				L. S. Acheson Bone Density and the Risk of Fractures: Should Treatment Thresholds Vary by Race? JAMA, May 4, 2005; 293(17): 2151 - 2154. [Full Text] [PDF]

				S. H. Ralston, N. Galwey, I. MacKay, O. M.E. Albagha, L. Cardon, J. E. Compston, C. Cooper, E. Duncan, R. Keen, B. Langdahl, et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study Hum. Mol. Genet., April 1, 2005; 14(7): 943 - 951. [Abstract] [Full Text] [PDF]

				L. Gennari, D. Merlotti, V. De Paola, A. Calabro, L. Becherini, G. Martini, and R. Nuti Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review Am. J. Epidemiol., February 15, 2005; 161(4): 307 - 320. [Abstract] [Full Text] [PDF]

				P.E. Norman and J.T. Powell Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 39 - 46. [Abstract] [Full Text] [PDF]

				J. P. A. Ioannidis, S. H. Ralston, S. T. Bennett, M. L. Brandi, D. Grinberg, F. B. Karassa, B. Langdahl, J. B. J. van Meurs, L. Mosekilde, S. Scollen, et al. Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes JAMA, November 3, 2004; 292(17): 2105 - 2114. [Abstract] [Full Text] [PDF]

				J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart 11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response Endocr. Rev., October 1, 2004; 25(5): 831 - 866. [Abstract] [Full Text] [PDF]

				J. Donath, G. Speer, G. Poor, P. Gergely Jr, A. Tabak, and P. Lakatos Vitamin D receptor, oestrogen receptor-{alpha} and calcium-sensing receptor genotypes, bone mineral density and biochemical markers in Paget's disease of bone Rheumatology, June 1, 2004; 43(6): 692 - 695. [Abstract] [Full Text] [PDF]

				Y. Kasukawa, D. J. Baylink, J. E. Wergedal, Y. Amaar, A. K. Srivastava, R. Guo, and S. Mohan Lack of Insulin-Like Growth Factor I Exaggerates the Effect of Calcium Deficiency on Bone Accretion in Mice Endocrinology, November 1, 2003; 144(11): 4682 - 4689. [Abstract] [Full Text] [PDF]

				F. Rivadeneira, J. J. Houwing-Duistermaat, N. Vaessen, J. M. Vergeer-Drop, A. Hofman, H. A. P. Pols, C. M. van Duijn, and A. G. Uitterlinden Association between an Insulin-Like Growth Factor I Gene Promoter Polymorphism and Bone Mineral Density in the Elderly: The Rotterdam Study J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3878 - 3884. [Abstract] [Full Text] [PDF]