Association of Common Vitamin D Receptor Gene Variations with Fracture Risk and Bone Mineral Density in Postmenopausal Korean Population

  • Hwang, Joo-Yeon (The Center for Genome Science, National Institute of Health) ;
  • Lee, Seung Hun (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Kim, Ghi-Su (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Koh, Jung-Min (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Go, Min-Jin (The Center for Genome Science, National Institute of Health) ;
  • Kim, Tae-Ho (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Hong, Jung-Min (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Park, Eui-Kyun (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Kim, Shin-Yoon (Deparement of Orthopedic Surgery, School of Medicine, Kyungpook National University) ;
  • Lee, Jong-Young (The Center for Genome Science, National Institute of Health)
  • Published : 2009.03.31


Osteoporosis is characterized by impaired osteogenesis. BMD is a major determinant of bone strength. The role of the VDR gene in predisposition to primary osteoporosis has been recognized. However, population-based case-control studies have been reported controversial results for known candidate genes in an ethnically distinct group. To determine the genetic effects of VDR variants on osteoporosis and BMD, we directly sequenced the VDR gene in 24 unrelated Korean individuals and identified eighteen sequence variants. We investigated the potential involvement of eight SNPs in osteoporosis in postmenopausal women (n = 729). Two SNPs (LD) in intron 2, -5294G>C (rs2238135) and -4817G>A (rs17882443) showed the evidence of association with enhanced BMD of the femoral neck ($p_{additive}$=0.031 for rs2238135; $p_{additive}$=0.017 and $p_{dominant}$= 0.019 for 17882443). Moreover, VDR -4817G>A was significantly associated with protective effect on all fracture risk ($p_{recessive}$=0.035, OR=0.2, 95% CI=$0.05{\sim}0.89$), and tended to be higher BMD values at various proximal femur sites. Therefore, we suggest that the -4817G>A may be useful genetic marker for vitamin D-related metabolism and may have an important role in the increased BMD of the proximal femur in postmenopausal Korean women.




  1. Horst-Sikorska, W., Kalak, R., Wawrzyniak, A., et al. (2007). Association analysis of the polymorphisms of the VDR gene with bone mineral density and the occurrence of fractures. J. Bone Miner Metab. 25, 310-319
  2. Kiel, D.P., Demissie, S., Dupuis, J., et al. (2007). Genomewide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet. Suppl:8-1, S14
  3. Long, J.R., Zhao, L.J., Liu, P.Y., et al. (2004). Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes. BMC Genet. 5, 11
  4. Mitra, S., Desai, M., and Ikram Khatkhatay, M., (2006). Vitamin D receptor gene polymorphisms and bone mineral density in postmenopausal Indian women. Maturitas 55, 27-35
  5. Morrison. N.A., Qi, J.C., Tokita, A., et al. (1994). Prediction of bone density from vitamin D receptor alleles. Nature 367, 284-287
  6. Zhang, Z.L., Qin, Y.J., Huang, Q.R., et al. (2004). Association of estrogen receptor-alpha and vitamin D receptor genotypes with therapeutic response to calcium in postmenopausal Chinese women. Acta Pharmacol Sin. 25, 1690-1697
  7. Baker, A.R., McDonnell, D.P., Hughes, M., et al. (1988). Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U.S.A. 85, 3294-3298
  8. Liel, Y., Edwards, J., Shary, J., et al. (1988). The effects of race and body habitus on bone mineral density of the radius, hip, and spine in premenopausal women. J. Clin Endocrinol Metab. 66, 1247-1250
  9. Uitterlinden, A.G., Ralston, S.H., Brandi, M.L., et al. (2006). The association between common vitamin D receptor gene variations and osteoporosis: a participant-level metaanalysis. Ann Intern Med. 145, 255-264
  10. Dvornyk, V., Long, J.R., Xiong, D.H., et al. (2004). Current limitations of SNP data from the public domain for studies of complex disorders: a test for ten candidate genes for obesity and osteoporosis. BMC Genet. 5, 4
  11. Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342
  12. Gordon, D., Abajian, C., and Green, P. (1998). Consed: a graphical tool for sequence finishing. Genome Res. 8, 195-202
  13. Morita, A., Iki, M., Dohi, Y., et al. (2004). Prediction of bone mineral density from vitamin D receptor polymorphisms is uncertain in representative samples of Japanese Women. The Japanese Population-based Osteoporosis (JPOS) Study. Int. J. Epidemiol. 33, 979-988
  14. Oliphant, A., Barker, D.L., Stuelpnagel, J.R., et al. (2002). BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques Suppl:56-8, 60-61
  15. Arden, N.K., and Spector, T.D. (1997). Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J. Bone Miner. Res. 12, 2076-2081
  16. Zmuda, J.M., Cauley, J.A., Danielson, M.E., et al. (1999). Vitamin D receptor translation initiation codon polymorphism and markers of osteoporotic risk in older African-American women. Osteoporos Int. 9, 214-219
  17. Kammerer, C.M., Dualan, A.A., Samollow, P.B., et al. (2004). Bone mineral density, carotid artery intimal medial thickness, and the vitamin D receptor BsmI polymorphism in Mexican American women. Calcif Tissue Int. 75, 292-298
  18. Ewing, B., Hillier, L., Wendl, M.C., et al.(1998). Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res. 8, 175-185
  19. Garnero, P., Borel, O., Sornay-Rendu, E., et al. (1995). Vitamin D receptor gene polymorphisms do not predict bone turnover and bone mass in healthy premenopausal women. J. Bone Miner. Res. 10, 1283-1288
  20. Harada, S., and Rodan, G.A. (2003). Control of osteoblast function and regulation of bone mass. Nature 423, 349-355
  21. Liu, Y.Z., Liu, Y.J., Recker, R.R., et al.(2003). Molecular studies of identification of genes for osteoporosis: the 2002 update. J. Endocrinol. 177, 147-196
  22. MacGregor, A., Snieder, H., and Spector, T.D. (2000). Genetic factors and osteoporotic fractures in elderly people. Twin data support genetic contribution to risk of fracture. BMJ 320, 1669-1670
  23. Burger, H., van Daele, P.L., Odding, E., et al. (1996). Association of radiographically evident osteoarthritis with higher bone mineral density and increased bone loss with age. The Rotterdam Study. Arthritis Rheum. 39, 81-86
  24. Langdahl, B.L., Gravholt, C.H., Brixen, K., et al. (2000). Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur. J. Clin. Invest. 30, 608-617
  25. Harris, S.S., Eccleshall, T.R., Gross, C., et al. (1997). The vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women. J. Bone Miner. Res. 12, 1043-1048
  26. Nickerson, D.A., Tobe, V.O., and Taylor, S.L. (1997). PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 25, 2745-2751
  27. Peacock, M. (1995). Vitamin D receptor gene alleles and osteoporosis: a contrasting view. J. Bone Miner. Res. 10, 1294-1297
  28. Khosla, S. (2001). Minireview: the OPG/RANKL/RANK system. Endocrinology 142,5050-5055
  29. Gueguen, R., Jouanny, P., Guillemin, F., et al. (1995). Segregation analysis and variance components analysis of bone mineral density in healthy families. J. Bone Miner. Res. 10, 2017-2022
  30. Eisman, J.A. (1999). Genetics of osteoporosis. Endocr Rev. 20, 788-804
  31. Hwang, J.Y., Lee, J.Y., Park, M.H., et al. (2006). Association of PLXNA2 polymorphisms with vertebral fracture risk and bone mineral density in postmenopausal Korean population. Osteoporos Int. 17, 1592-1601
  32. Yamada, Y., Ando, F., Niino, N., et al. (2003). Association of polymorphisms of interleukin-6, osteocalcin, and vitamin D receptor genes, alone or in combination, with bone mineral density in community-dwelling Japanese women and men. J. Clin. Endocrinol Metab. 88, 3372-3378
  33. Deng, H.W., Li, J., Li, J.L., et al. (1999). Association of VDR and estrogen receptor genotypes with bone mass in postmenopausal Caucasian women: different conclusions with different analyses and the implications. Osteoporos Int. 9,499-507
  34. Deng, H.W., Chen, W.M., 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
  35. Quesada, J.M., Casado, A., Diaz, C., et al. (2004). Allele-frequency determination of BsmI and FokI polymorphisms of the VDR gene by quantitative real-time PCR (QRT-PCR) in pooled genomic DNA samples. J. Steroid Biochem Mol Biol. 89-90, 209-214
  36. Oldroyd, B., Smith, A.H., and Truscott, J.G. (2003). Cross-calibration of GE/Lunar pencil and fan-beam dual energy densitometers--bone mineral density and body composition studies. Eur. J. Clin. Nutr. 57, 977-987
  37. Wang, M.C., Aguirre, M., Bhudhikanok, G.S., et al. (1997). Bone mass and hip axis length in healthy Asian, black, Hispanic, and white American youths. J. Bone Miner Res. 12, 1922-1935
  38. McClure, L., Eccleshall, T.R., Gross, C., et al. (1997). Vitamin D receptor polymorphisms, bone mineral density, and bone metabolism in postmenopausal Mexican-American women. J. Bone Miner. Res. 12, 234-240
  39. Ng, M.Y., Sham, P.C., Paterson, A.D., et al. (2006). Effect of environmental factors and gender on the heritability of bone mineral density and bone size. Ann. Hum. Genet. 70, 428-438