Skip to main content
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2005 Mar;42(3):240–246. doi: 10.1136/jmg.2004.023895

Association of oestrogen receptor α gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone

O Albagha 1, U Pettersson 1, A Stewart 1, F McGuigan 1, H MacDonald 1, D Reid 1, S Ralston 1
PMCID: PMC1736016  PMID: 15744038

Abstract

Background: The gene encoding oestrogen receptor α (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.

Objective: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.

Results: There was a significant association between a common haplotype "px", defined by the PvuII andXbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were ∼14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.

Conclusions: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

Full Text

The Full Text of this article is available as a PDF (138.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albagha O. M., McGuigan F. E., Reid D. M., Ralston S. H. Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res. 2001 Jan;16(1):128–134. doi: 10.1359/jbmr.2001.16.1.128. [DOI] [PubMed] [Google Scholar]
  2. Albagha Omar M. E., Tasker Paul N., McGuigan Fiona E. A., Reid David M., Ralston Stuart H. Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women. Hum Mol Genet. 2002 Sep 15;11(19):2289–2295. doi: 10.1093/hmg/11.19.2289. [DOI] [PubMed] [Google Scholar]
  3. Arden N. K., Baker J., Hogg C., Baan K., Spector T. D. The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res. 1996 Apr;11(4):530–534. doi: 10.1002/jbmr.5650110414. [DOI] [PubMed] [Google Scholar]
  4. Arden N. K., Spector T. D. Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res. 1997 Dec;12(12):2076–2081. doi: 10.1359/jbmr.1997.12.12.2076. [DOI] [PubMed] [Google Scholar]
  5. Bagger Y. Z., Jørgensen H. L., Heegaard A. M., Bayer L., Hansen L., Hassager C. No major effect of estrogen receptor gene polymorphisms on bone mineral density or bone loss in postmenopausal Danish women. Bone. 2000 Feb;26(2):111–116. doi: 10.1016/s8756-3282(99)00261-6. [DOI] [PubMed] [Google Scholar]
  6. Bauer D. C., Glüer C. C., Cauley J. A., Vogt T. M., Ensrud K. E., Genant H. K., Black D. M. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. A prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med. 1997 Mar 24;157(6):629–634. [PubMed] [Google Scholar]
  7. Becherini L., Gennari L., Masi L., Mansani R., Massart F., Morelli A., Falchetti A., Gonnelli S., Fiorelli G., Tanini A. Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women. Hum Mol Genet. 2000 Aug 12;9(13):2043–2050. doi: 10.1093/hmg/9.13.2043. [DOI] [PubMed] [Google Scholar]
  8. Cummings S. R., Black D. M., Nevitt M. C., Browner W., Cauley J., Ensrud K., Genant H. K., Palermo L., Scott J., Vogt T. M. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 1993 Jan 9;341(8837):72–75. doi: 10.1016/0140-6736(93)92555-8. [DOI] [PubMed] [Google Scholar]
  9. Danielson M. E., Cauley J. A., Baker C. E., Newman A. B., Dorman J. S., Towers J. D., Kuller L. H. Familial resemblance of bone mineral density (BMD) and calcaneal ultrasound attenuation: the BMD in mothers and daughters study. J Bone Miner Res. 1999 Jan;14(1):102–110. doi: 10.1359/jbmr.1999.14.1.102. [DOI] [PubMed] [Google Scholar]
  10. Deng H. W., Li J., Li J. L., Johnson M., Gong G., Davis K. M., Recker R. R. Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes. Hum Genet. 1998 Nov;103(5):576–585. doi: 10.1007/s004390050872. [DOI] [PubMed] [Google Scholar]
  11. Devoto M., Shimoya K., Caminis J., Ott J., Tenenhouse A., Whyte M. P., Sereda L., Hall S., Considine E., Williams C. J. 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. 1998 Mar-Apr;6(2):151–157. doi: 10.1038/sj.ejhg.5200169. [DOI] [PubMed] [Google Scholar]
  12. Garton M. J., Torgerson D. J., Donaldson C., Russell I. T., Reid D. M. Recruitment methods for screening programmes: trial of a new method within a regional osteoporosis study. BMJ. 1992 Jul 11;305(6845):82–84. doi: 10.1136/bmj.305.6845.82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giguère Y., Dodin S., Blanchet C., Morgan K., Rousseau F. The association between heel ultrasound and hormone replacement therapy is modulated by a two-locus vitamin D and estrogen receptor genotype. J Bone Miner Res. 2000 Jun;15(6):1076–1084. doi: 10.1359/jbmr.2000.15.6.1076. [DOI] [PubMed] [Google Scholar]
  14. Grant S. F., Reid D. M., Blake G., Herd R., Fogelman I., Ralston S. H. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet. 1996 Oct;14(2):203–205. doi: 10.1038/ng1096-203. [DOI] [PubMed] [Google Scholar]
  15. Guéguen R., Jouanny P., Guillemin F., Kuntz C., Pourel J., Siest G. Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Miner Res. 1995 Dec;10(12):2017–2022. doi: 10.1002/jbmr.5650101223. [DOI] [PubMed] [Google Scholar]
  16. Han K., Choi J., Moon I., Yoon H., Han I., Min H., Kim Y., Choi Y. Non-association of estrogen receptor genotypes with bone mineral density and bone turnover in Korean pre-, peri-, and postmenopausal women. Osteoporos Int. 1999;9(4):290–295. doi: 10.1007/s001980050150. [DOI] [PubMed] [Google Scholar]
  17. Hans D., Arlot M. E., Schott A. M., Roux J. P., Kotzki P. O., Meunier P. J. Do ultrasound measurements on the os calcis reflect more the bone microarchitecture than the bone mass?: a two-dimensional histomorphometric study. Bone. 1995 Mar;16(3):295–300. doi: 10.1016/8756-3282(94)00041-7. [DOI] [PubMed] [Google Scholar]
  18. Hans D., Dargent-Molina P., Schott A. M., Sebert J. L., Cormier C., Kotzki P. O., Delmas P. D., Pouilles J. M., Breart G., Meunier P. J. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 1996 Aug 24;348(9026):511–514. doi: 10.1016/s0140-6736(95)11456-4. [DOI] [PubMed] [Google Scholar]
  19. Herrington David M., Howard Timothy D., Brosnihan K. Bridget, McDonnell Donald P., Li Xiaolin, Hawkins Gregory A., Reboussin David M., Xu Jianfeng, Zheng Siqun L., Meyers Deborah A. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002 Apr 23;105(16):1879–1882. doi: 10.1161/01.cir.0000016173.98826.88. [DOI] [PubMed] [Google Scholar]
  20. Howard G. M., Nguyen T. V., Harris M., Kelly P. J., Eisman J. A. Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study. J Bone Miner Res. 1998 Aug;13(8):1318–1327. doi: 10.1359/jbmr.1998.13.8.1318. [DOI] [PubMed] [Google Scholar]
  21. Ioannidis John P. A., Stavrou Ioanna, Trikalinos Thomas A., Zois Christos, Brandi Maria Luisa, Gennari Luigi, Albagha Omar, Ralston Stuart H., Tsatsoulis Agathocles, ER-alpha Genetics Meta-Analysis Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res. 2002 Nov;17(11):2048–2060. doi: 10.1359/jbmr.2002.17.11.2048. [DOI] [PubMed] [Google Scholar]
  22. Kanis J. A., Melton L. J., 3rd, Christiansen C., Johnston C. C., Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994 Aug;9(8):1137–1141. doi: 10.1002/jbmr.5650090802. [DOI] [PubMed] [Google Scholar]
  23. Karasik D., Myers R. H., Cupples L. A., Hannan M. T., Gagnon D. R., Herbert A., Kiel D. P. Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study. J Bone Miner Res. 2002 Sep;17(9):1718–1727. doi: 10.1359/jbmr.2002.17.9.1718. [DOI] [PubMed] [Google Scholar]
  24. Karasik D., Myers R. H., Hannan M. T., Gagnon D., McLean R. R., Cupples L. A., Kiel D. P. Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis. Osteoporos Int. 2002 Oct;13(10):796–802. doi: 10.1007/s001980200110. [DOI] [PubMed] [Google Scholar]
  25. Khaw Kay-Tee, Reeve Jonathan, Luben Robert, Bingham Sheila, Welch Ailsa, Wareham Nicholas, Oakes Suzy, Day Nicholas. Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study. Lancet. 2004 Jan 17;363(9404):197–202. doi: 10.1016/S0140-6736(03)15325-1. [DOI] [PubMed] [Google Scholar]
  26. Kobayashi S., Inoue S., Hosoi T., Ouchi Y., Shiraki M., Orimo H. Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res. 1996 Mar;11(3):306–311. doi: 10.1002/jbmr.5650110304. [DOI] [PubMed] [Google Scholar]
  27. Koh Jung-Min, Nam-Goong Il Seong, Hong Jeong Soo, Kim Hong-Kyu, Kim Jae Seung, Kim Shin-Yoon, Kim Ghi Su. Oestrogen receptor alpha genotype, and interactions between vitamin D receptor and transforming growth factor-beta1 genotypes are associated with quantitative calcaneal ultrasound in postmenopausal women. Clin Endocrinol (Oxf) 2004 Feb;60(2):232–240. doi: 10.1046/j.1365-2265.2003.01972.x. [DOI] [PubMed] [Google Scholar]
  28. Koller D. L., Econs M. J., Morin P. A., Christian J. C., Hui S. L., Parry P., Curran M. E., Rodriguez L. A., Conneally P. M., Joslyn G. Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis. J Clin Endocrinol Metab. 2000 Sep;85(9):3116–3120. doi: 10.1210/jcem.85.9.6778. [DOI] [PubMed] [Google Scholar]
  29. Maruyama H., Toji H., Harrington C. R., Sasaki K., Izumi Y., Ohnuma T., Arai H., Yasuda M., Tanaka C., Emson P. C. Lack of an association of estrogen receptor alpha gene polymorphisms and transcriptional activity with Alzheimer disease. Arch Neurol. 2000 Feb;57(2):236–240. doi: 10.1001/archneur.57.2.236. [DOI] [PubMed] [Google Scholar]
  30. Mizunuma H., Hosoi T., Okano H., Soda M., Tokizawa T., Kagami I., Miyamoto S., Ibuki Y., Inoue S., Shiraki M. Estrogen receptor gene polymorphism and bone mineral density at the lumbar spine of pre- and postmenopausal women. Bone. 1997 Nov;21(5):379–383. doi: 10.1016/s8756-3282(97)00178-6. [DOI] [PubMed] [Google Scholar]
  31. Patel M. S., Cole D. E., Smith J. D., Hawker G. A., Wong B., Trang H., Vieth R., Meltzer P., Rubin L. A. Alleles of the estrogen receptor alpha-gene and an estrogen receptor cotranscriptional activator gene, amplified in breast cancer-1 (AIB1), are associated with quantitative calcaneal ultrasound. J Bone Miner Res. 2000 Nov;15(11):2231–2239. doi: 10.1359/jbmr.2000.15.11.2231. [DOI] [PubMed] [Google Scholar]
  32. Perneger T. V. What's wrong with Bonferroni adjustments. BMJ. 1998 Apr 18;316(7139):1236–1238. doi: 10.1136/bmj.316.7139.1236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Porter R. W., Miller C. G., Grainger D., Palmer S. B. Prediction of hip fracture in elderly women: a prospective study. BMJ. 1990 Sep 29;301(6753):638–641. doi: 10.1136/bmj.301.6753.638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Salmén T., Heikkinen A. M., Mahonen A., Kröger H., Komulainen M., Saarikoski S., Honkanen R., Mäenpä P. H. Early postmenopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in Finnish women: effect of hormone replacement therapy. J Bone Miner Res. 2000 Feb;15(2):315–321. doi: 10.1359/jbmr.2000.15.2.315. [DOI] [PubMed] [Google Scholar]
  35. Smith D. M., Nance W. E., Kang K. W., Christian J. C., Johnston C. C., Jr Genetic factors in determining bone mass. J Clin Invest. 1973 Nov;52(11):2800–2808. doi: 10.1172/JCI107476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Stephens M., Smith N. J., Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001 Mar 9;68(4):978–989. doi: 10.1086/319501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Styrkarsdottir Unnur, Cazier Jean-Baptiste, Kong Augustine, Rolfsson Ottar, Larsen Helene, Bjarnadottir Emma, Johannsdottir Vala D., Sigurdardottir Margret S., Bagger Yu, Christiansen Claus. Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol. 2003 Nov 3;1(3):E69–E69. doi: 10.1371/journal.pbio.0000069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Torgerson D. J., Campbell M. K., Thomas R. E., Reid D. M. Prediction of perimenopausal fractures by bone mineral density and other risk factors. J Bone Miner Res. 1996 Feb;11(2):293–297. doi: 10.1002/jbmr.5650110219. [DOI] [PubMed] [Google Scholar]
  39. Vandevyver C., Vanhoof J., Declerck K., Stinissen P., Vandervorst C., Michiels L., Cassiman J. J., Boonen S., Raus J., Geusens P. Lack of association between estrogen receptor genotypes and bone mineral density, fracture history, or muscle strength in elderly women. J Bone Miner Res. 1999 Sep;14(9):1576–1582. doi: 10.1359/jbmr.1999.14.9.1576. [DOI] [PubMed] [Google Scholar]
  40. Willing M., Sowers M., Aron D., Clark M. K., Burns T., Bunten C., Crutchfield M., D'Agostino D., Jannausch M. Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction. J Bone Miner Res. 1998 Apr;13(4):695–705. doi: 10.1359/jbmr.1998.13.4.695. [DOI] [PubMed] [Google Scholar]
  41. Wilson S. G., Reed P. W., Andrew T., Barber M. J., Lindersson M., Langdown M., Thompson D., Thompson E., Bailey M., Chiano M. A genome-screen of a large twin cohort reveals linkage for quantitative ultrasound of the calcaneus to 2q33-37 and 4q12-21. J Bone Miner Res. 2003 Dec 16;19(2):270–277. doi: 10.1359/JBMR.0301224. [DOI] [PubMed] [Google Scholar]
  42. Wilson S. G., Reed P. W., Bansal A., Chiano M., Lindersson M., Langdown M., Prince R. L., Thompson D., Thompson E., Bailey M. Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36. Am J Hum Genet. 2002 Dec 11;72(1):144–155. doi: 10.1086/345819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. van Meurs Joyce B. J., Schuit Stephanie C. E., Weel Angélique E. A. M., van der Klift Marjolein, Bergink Arjan P., Arp Pascal P., Colin Edgar M., Fang Yue, Hofman Albert, van Duijn Cornelia M. Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Hum Mol Genet. 2003 Jul 15;12(14):1745–1754. doi: 10.1093/hmg/ddg176. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES