Advertisement

Genes and Osteoporosis

  • Stuart H. Ralston

Summary

  • Genetic factors play an important role in the regulation of bone mass and in the pathogenesis of osteoporosis. Twin and family studies have shown that 50–85% of the variance in BMD is determined genetically, and molecular genetic studies have identified several candidate genes and quantitative trait loci that are involved in this process.

  • The most widely studied candidate genes are the vitamin D receptor (VDR) gene, the estrogen receptor alpha gene, and the COLIA1 gene, which encodes the alpha 1 chain of type I collagen. There is evidence to suggest that allelic variation in all three genes plays a role in regulating BMD, but the effects are modest and together probably account for less than 5% of the heritable contribution to BMD. The COLlAI Sp1 binding site polymorphism acts as a marker for osteoporotic fractures, independent from its association with BMD, and is associated with altered collagen production by bone cells and reduced bone strength.

  • Linkage studies support the view that BMDregulation is under polygenic control in that they have identified multiple quantitative trait loci for regulation of BMD in humans and experimental animals.

  • Most of the genes responsible for the heritable component of BMD regulation and genetic effects on fracture risk remain to be discovered. When this information becomes available, it is likely that genetic testing for candidate gene polymorphisms will be used clinically in the assessment of osteoporotic fracture risk and in predicting treatment response.

Keywords

Bone Mineral Density Quantitative Trait Locus Bone Mass Osteoporotic Fracture Osteogenesis Imperfecta 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Further Reading

  1. Arai H, Miyamoto K-I, Taketani Y, et al. (1997) A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 12: 915-921.Google Scholar
  2. Arai H, Miyamoto KI, Yoshida M, et al. (2001) The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 16: 1256–1264.Google Scholar
  3. Arden NK, Spector TD (1997) Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res 12: 2076–2081.PubMedCrossRefGoogle Scholar
  4. Arden NK, Baker J, Hogg C, Baan K, Spector TD (1996) The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res 11: 530–534.PubMedCrossRefGoogle Scholar
  5. Beamer WG, Shultz KL, Churchill GA, et al. (1999) Quantitative trait loci for bone density in C57BLl6J and CAST/EiJ inbred mice. Mamm Genome 10: 1043–1049.Google Scholar
  6. Cooper GS, Umbach DM (1996) Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res 11: 1841–1849.PubMedCrossRefGoogle Scholar
  7. Cummings SR, Nevitt MC, Browner WS, et al. (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332: 767–773.Google Scholar
  8. Deng HW, Chen WM, Recker S, et al. (2000) Genetic determination of Colles’ fracture and differential bone mass in women with and without Colles’ fracture. J Bone Miner Res 15: 1243–1252.Google Scholar
  9. Devoto M, Shimoya K, Caminis J, et al. (1998) First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet 6: 151–157.Google Scholar
  10. Garnero P, Arden NK, Griffiths G, Delmas PD, Spector TD (1996) Genetic influence on bone turnover in postmenopausal twins. J Clin Endocrinol Metab 81: 140–146.PubMedCrossRefGoogle Scholar
  11. Gong Y, Slee RB, et al. (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107: 513–523.Google Scholar
  12. Grant SFA, Reid DM, Blake G, et al. (1996). Reduced bone density and osteoporosis associated with a polymorphic Spl site in the collagen type I alpha 1 gene. Nat Genet 14: 203–205.Google Scholar
  13. Gueguen R, Jouanny P, Guillemin F, Kuntz C, Pourel J, Siest G (1995) Segregation analysis and variance components analys is of bone mineral density in healthy families. J Bone Miner Res 12: 2017–2022.Google Scholar
  14. Kannus P, Palvanen M, Kaprio J, Parkkari J, Koskenvuo M (1999) Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twins. Br Med J 319: 1334–13.CrossRefGoogle Scholar
  15. Kaprio J, Rimpela A, Winter T, Viken RJ, Rimpela M, Rose RJ (1995) Common genetic influences on BMI and age at menarche. Hum Biol 67: 739–753.PubMedGoogle Scholar
  16. Keen RW, Hart DJ, Arden NK, Doyle DV, Spector TD (1999) Family history of appendicular fracture and risk of osteoporosis: a population-based study. Osteoporos Int 10: 161–166.PubMedCrossRefGoogle Scholar
  17. Klein RF, Mitchell SR, Phillips TJ, Belknap JK, Orwoll ES (1998) Genetic analysis of bone mass in mice. J Bone Miner Res 13: 1648–1656.PubMedCrossRefGoogle Scholar
  18. Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H (1996) Association of bone mineral density with polymorphisms of the estrogen receptor gene in postmenopausal women. J Bone Miner Res 11: 306–311.PubMedCrossRefGoogle Scholar
  19. Koller DL, Econs MJ, Morin PA, et al. (2000) Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis. J Clin Endocrinol Metab 85: 3116–3120.Google Scholar
  20. Koller DL, Liu G, Econs MJ, et al. (2001) Genome screen for quantitative trait loci underlying normal variation in femoral structure. J Bone Miner Res 16: 985–991.Google Scholar
  21. Krall EA, Dawson-Hughes B (1993) Heritable and life-style determinants of bone mineral density. J Bone Miner Res 8: 1–9.PubMedCrossRefGoogle Scholar
  22. Mann V, Hobson EE, Li B, et al. (2001). A COLIA1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 107: 899–907.Google Scholar
  23. McGuigan FE, Armbrecht G, Smith R, Felsenberg D, Reid DM, Ralston SH (2001) Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women. Osteoporos Int 12: 91–96.PubMedCrossRefGoogle Scholar
  24. Morrison NA, Qi JC, Tokita A, et al. (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367: 284–287.Google Scholar
  25. Nui T, Chen C, Cordell H, et al. (1999) A genome-wide scan for loci linked to forearm bone mineral density. Hum Genet 104: 226–233.Google Scholar
  26. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults: a twin study. J Clin Invest 80: 706–710.PubMedCrossRefGoogle Scholar
  27. Ralston SH (1999) The genetics of osteoporosis. Bone 25: 85–86.PubMedCrossRefGoogle Scholar
  28. Rowe DW (1991) Osteogenesis imperfecta. In: Heersche JNM, Kanis JA (eds). Bone and Mineral Research. Amsterdam: Elsevier, pp. 209–241.Google Scholar
  29. Shimizu M, Higuchi K, Bennett B, et al. (1999) Identification of peak bone mass QTL in a spontaneously osteoporotic mouse strain. Mamm Genome 10: 81–87.Google Scholar
  30. Shrnookler-Reis RJ, Benes H, McClure T, et al. (1999). Genetic mapp ing of loci conferring osteopenia using closely-related mouse strains. J Bone Miner Res 13: 1035.Google Scholar
  31. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC (1973) Genetic factors in determining bone mass. J Clin Invest 52: 2800–2808.PubMedCrossRefGoogle Scholar
  32. Snieder H, MacGregor AJ, and Spector TD (1998) Genes control the cessation of a woman’s reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 83: 1875–1880.PubMedCrossRefGoogle Scholar
  33. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52: 506–516.PubMedGoogle Scholar
  34. Spotila LD, Devoto M, Caminis J, et al. (1998) Suggested linkage of low bone density to chromosome 1p36 is extended to a second cohort of sib pairs. Bone 23 (supplement 5): S277.Google Scholar
  35. Torgerson DJ, Campbell MK, Thomas RE, Reid DM (1996) Prediction of perimenopausal fractures by bone mineral density and other risk factors. J Bone Miner Res 11: 293–297.PubMedCrossRefGoogle Scholar
  36. Weel AM, Uitterlinden AG, Burger H, et al. (1999) Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab 84: 3146–3150.Google Scholar

Copyright information

© Springer-Verlag London 2004

Authors and Affiliations

  • Stuart H. Ralston

There are no affiliations available

Personalised recommendations