Calcified Tissue International

, Volume 77, Issue 3, pp 152–159

Genetic Polymorphisms of OPG, RANK, and ESR1 and Bone Mineral Density in Korean Postmenopausal Women

  • J. Y. Choi
  • A. Shin
  • S. K. Park
  • H. W. Chung
  • S.I. Cho
  • C. S. Shin
  • H. Kim
  • K. M. Lee
  • K. H. Lee
  • C. Kang
  • D. Y. Cho
  • D. Kang


To evaluate the effects of genetic polymorphisms of OPG, RANK, and ESR1, which regulate osteoclastogenesis, on bone mineral density (BMD), a cross-sectional study was conducted in 650 Korean postmenopausal women. BMDs of the distal radius and the calcaneus were measured by dual energy X-ray absorptiometry (DXA). Genetic polymorphisms of OPG 163 A > G, 1181 G > C; RANK 421 C > T, 575 T > C; and ESR1 1335 C > T, 2142 G > A were determined by matrix-assisted laser desorption/ionization—time of flight (MALDI-ToF) mass spectrometry. The differences between the BMDs of the genotypes of OPG, RANK, and ESR1 were analyzed by multiple linear regression model adjusted for age and body mass index. Women with the OPG 1181 CC genotype had higher BMDs at the distal radius (7%) and calcaneus (10%) than those with the GG genotype; and these differences were statistically significant (P = 0.001 and P = 0.007, respectively). A significant association was also observed between RANK 575 T > C and calcaneus BMD (P for trend = 0.017). No significant association was observed between BMDs and the polymorphisms of ESR1. The association between OPG 1181 G > C and BMD was profound in subjects with the RANK 575 TT or ESR1 2142 GG genotypes; women with OPG 1181 CC had higher BMDs at the distal radius (11%) and calcaneus (11%) than those with OPG 1181 GG only in women with RANK 575 TT genotype (P = 0.002 and P = 0.021, respectively). These results suggest that OPG genetic polymorphisms, especially with the RANK 575 TT or ESR1 2142 GG genotypes, are related to low BMD in postmenopausal Korean women.

Key words

OPG-RANK Bone mineral density Genetic polymorphism 


  1. 1.
    NIH consensus conference (2001) Osteoporosis prevention, diagnosis, and therapy. J Am Med Assoc 285:785–795Google Scholar
  2. 2.
    Ammann P, Rizzoli R (2003) Bone strength and its determinants. Osteoporosis Int 14(Suppl 3):S13–S18CrossRefGoogle Scholar
  3. 3.
    Eisman JA (1999) Genetics of Osteoporosis. Endocr Rev 20:788–804CrossRefPubMedGoogle Scholar
  4. 4.
    Ralston SH (2002) Genetic control of susceptibility to Osteoporosis. J Clin Endocr Metab 87:2460–2466CrossRefPubMedGoogle Scholar
  5. 5.
    Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4:638–649CrossRefPubMedGoogle Scholar
  6. 6.
    Aubin JE, Bonnelye E (2000) Osteopretegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Osteoporosis Int 11:905–913CrossRefGoogle Scholar
  7. 7.
    Khosia S, Melton LJ, Riggs BL (2002) Estrogen and the male skeleton. J Clin Endocr Metab 87:1443–1450CrossRefPubMedGoogle Scholar
  8. 8.
    Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL (1999) Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140:4367–4370CrossRefPubMedGoogle Scholar
  9. 9.
    Shevde NK, Bendixen AC, Dienger KM, Pike JW (2000) Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 97:7828–7834CrossRefGoogle Scholar
  10. 10.
    Saika M, Inoue D, Kido S, Matsumoto T (2001) 17beta-estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-alpha. Endocrinology 142:2205–2212CrossRefPubMedGoogle Scholar
  11. 11.
    Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL (2003) Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 111:1221–1230CrossRefPubMedGoogle Scholar
  12. 12.
    Arko B, Prezelj J, Komel R, Kocijancic A, Marc J (2002) Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocr Metab 87:4080–4084CrossRefPubMedGoogle Scholar
  13. 13.
    Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF (2002) Polymorphisms in the osteoprotegrin gene are associated with osteoporotic fractures. J Bone Miner Res 17:1245–1255PubMedGoogle Scholar
  14. 14.
    Ohmori H, Makita Y, Funamizu K, Hirooka K, Hosoi T, Orimo H, Suzuki T, Ikari K, Nakajima T, Inoue I, Hata A (2000) Linkage and association analyses of the osteoprotegerin gene locus with human osteoporosis. J Hum Genet 47:400–406CrossRefGoogle Scholar
  15. 15.
    Wynne F, Drummond F, O’Sullivan K, Daly M, Shanahan F, Molloy MG, Quane KA (2002) Investigation of the genetic influence of the OPG, VDR (FokI), and COL1A1 Sp1 polymorphisms on BMD in the Irish population. Calcif Tissue Int 71:26–35CrossRefPubMedGoogle Scholar
  16. 16.
    Yamada Y, Ando F, Niino N, Shimokata H (2003) Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Molec Genet Metab 80:344–349CrossRefGoogle Scholar
  17. 17.
    Brandstrom H, Gerdhem P, Stiger F, Obrant KJ, Melhus H, Ljunggren O, Kindmark A, Akesson K (2004) Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women. Calcif Tissue Int 74:18–24CrossRefPubMedGoogle Scholar
  18. 18.
    Jorgensen HL, Kusk P, Madsen B, Fenger M, Lauritzen J (2004) Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios. J Bone Miner Metab 22:132–138CrossRefPubMedGoogle Scholar
  19. 19.
    Wuyts W, Van Wesenbeeck L, Morales-Piga A, Ralston S, Hocking L, Vanhoenacker F, Westhovens R, Verbruggen L, Anderson D, Hughes A, Van Hul W (2001) Evaluation of the role of RANK and OPG genes in Paget’s disease of bone. Bone 28:104–107CrossRefPubMedGoogle Scholar
  20. 20.
    Ioannidis JP, Stavrou I, Trikalinos TA, Zois C, Brandi ML, Gennari L, Albagha O, Ralston SH, Tsatsoulis A (2002) Association of polymorphisms of the estrogen receptor α gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 17:2048–2060PubMedGoogle Scholar
  21. 21.
    Han K, Choi J, Moon I, Yoon H, Han I, Min H, Kirn Y, Choi Y (1999) Non-association of estrogen receptor genotypes with bone mineral density and bone turnover in Korean pre-, peri-, and postmenopausal women. Osteoporosis Int 9:290–295CrossRefGoogle Scholar
  22. 22.
    Kim JG, Lim KS, Kim EK, Choi YM, Lee JY (2001) Association of vitamin D receptor and estrogen receptor gene polymorphisms with bone mass in postmenopausal Korean women. Menopause 8:222–228CrossRefPubMedGoogle Scholar
  23. 23.
    Ioannidis JPA, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OME, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JPTM, Mavilia C, Masi L, McGuigan FEA, Nogues X, Pols HAP, Reid DM, Schuit SCE, Sherlock RE, Uitterlinden AG (2004) Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114CrossRefPubMedGoogle Scholar
  24. 24.
    Jurada S, Marc J, Prezelj J, Kocijancic A, Komel R (2001) Codon 325 sequence polymorphism of the estrogen receptor gene and bone mineral density in postmenopausal women. J Steroid Biochem 78:15–20CrossRefGoogle Scholar
  25. 25.
    Ongphiphadhanakul B, Chanprasertyothin S, Payattikul P, Saetung S, Piaseu N, Chailurkit L, Rajatanavin R (2001) Association of a G2014A transition in exon 8 of estrogen receptor-α gene with postmenopausal osteoporosis. Osteoporosis Int 12:1015–1019CrossRefGoogle Scholar
  26. 26.
    Hoshino S, Hosoi T, Miyao M, Shiraki M, Orimo H, Ouchi Y, Inoue S (2000) Identification of a novel polymorphism of estrogen receptor-α gene that is associated with calcium excretion in urine. J Bone Miner Metab 18:153–157CrossRefPubMedGoogle Scholar
  27. 27.
    Shin A, Choi JY, Chung HW, Park SK, Shin CS, Choi YH, Cho SI, Kim DS, Kim DI, Lee KM, Lee KH, Yoo KY, Kang D (2004) Prevalence and risk factors of distal forearm and calcaneus bone mineral density in Korean population. Osteoporosis Int 15: 639–644CrossRefGoogle Scholar
  28. 28.
    Shepherd JA, Cheng XG, Lu Y, Njeh C, Toschke J, Engelke K, Grigorian M, Genant HK (2002) Universal standardization of forearm bone densitometry. J Bone Miner Res 17:734–745PubMedGoogle Scholar
  29. 29.
    Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction. Am J Hum Genet 73:1162–1169CrossRefPubMedGoogle Scholar
  30. 30.
    Lewontin RC (1988) On measures of gametic disequilibrium. Genetics 120:849–852PubMedGoogle Scholar
  31. 31.
    Uitterlinden AG, Weel AEAM, Burger H, Fang Y, van Duijn CM, Hofman A, van Leeuwen JPTM, Pols HAP (2001) Interaction between the vitatmin D receptor gene and collagen type Iα1 gene in susceptibility of fracture. J Bone Miner Res 16:379–385PubMedGoogle Scholar
  32. 32.
    Colin EM, Uitterlinden AG, Meurs JBJ, Bergink AP, van de Klift M, Fang Y, Arp PP, Hofman A, van Leeuwen JPTM, Pols HAP (2003) Interaction between vitamin D receptor genotype and estrogen receptor α genotype influences vertebral fracture risk. J Clin Endocrinol Metab 88:3777–3784CrossRefPubMedGoogle Scholar
  33. 33.
    Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner W, Nevitt M, Cummings SR (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the study of osteoporotic fractures. J Bone Miner Res 18:1947–1954PubMedGoogle Scholar
  34. 34.
    Sweeney AT, Malabanan AO, Blake MA, Weinberg J, Turner A, Ray P, Holick MF (2002) Bone mineral density assessment: comparison of dual-energy X-ray absorptiometry measurements at the calcaneus, spine, and hip. J Clin Densitom 5:57–62CrossRefPubMedGoogle Scholar
  35. 35.
    Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefPubMedGoogle Scholar

Copyright information

©  Springer Science+Business Media, Inc.  2005

Authors and Affiliations

  • J. Y. Choi
    • 1
  • A. Shin
    • 2
  • S. K. Park
    • 3
  • H. W. Chung
    • 4
  • S.I. Cho
    • 5
  • C. S. Shin
    • 6
  • H. Kim
    • 5
  • K. M. Lee
    • 1
  • K. H. Lee
    • 1
  • C. Kang
    • 7
  • D. Y. Cho
    • 8
  • D. Kang
    • 1
    • 9
  1. 1.Department of Preventive Medicine Seoul National University College of MedicineSeoulKorea
  2. 2.Center for Health Services ResearchVanderbilt UniversityUSA
  3. 3.Department of Preventive Medicine Konkuk University College of Medicine ChungjuKorea
  4. 4.Department of Obstetrics and Gynecology Ewha Womans University College of MedicineKorea
  5. 5.Department of Epidemiology and Biostatistics and Institute of Public health and Enviornmental Sciences, School of Public Health Seoul National UniversitySouth Korea
  6. 6.Department of Internal Medicine Seoul National University College of MedicineKorea
  7. 7.Department of Biological ScienceKAISTKorea
  8. 8.Clinical Research Institute Labgenomics Co., LtdKorea
  9. 9.Cancer Research Institute Seoul National University College of MedicineKorea

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