Osteoporosis International

, Volume 16, Issue 12, pp 1519–1524

The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women

  • Hong-yan Zhao
  • Jian-min Liu
  • Guang Ning
  • Yong-ju Zhao
  • Lian-zhen Zhang
  • Li-hao Sun
  • Man-yin Xu
  • A. G. Uitterlinden
  • Jia-lun Chen
Original Article

Abstract

The objective was to identify single nucleotide polymorphisms (SNPs) in exons of the osteoprotegerin gene and to analyze the relationship between the SNPs and bone mineral density in postmenopausal women. We used polymerase chain reaction (PCR) and direct sequencing methods to identify SNPs and genotypes in 205 postmenopausal women. BMD at the lumbar spine (L2–4) and femoral neck (FN) were measured by dual-energy X-ray absorptiometry (DEXA). Serum osteocalcin (OC), osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL) and urinary N-telopeptide of type I collagen (NTx) were also measured. In exon 1 of the OPG gene, we found the Lys3Asn SNP. In 205 postmenopausal women, the Asn-allele frequency was 26.0%, and the distribution of Lys3Asn genotypes was Lys-Lys 56.6%, Lys-Asn 34.6% and Asn-Asn 8.8%, respectively. BMD at the lumbar spine (L2–4) of the Asn-Asn genotype was significantly higher (9.5–12.6%) than Lys-Asn and Lys-Lys genotypes ( P =0.012), with evidence for an allele dose effect ( P =0.008). Results remained similar after adjustment for age and body mass index. The Lys3Asn polymorphism of the OPG gene alone accounted for 7.7% of the variance of the L2–4 BMD in a multiple regression model. Logistic regression analysis revealed that the OPG genotype Lys-Lys had a 2.7 times (95% CI: 0.83–9.11) greater risk for osteopenia/osteoporosis than the Asn-Asn genotype. The Lys3Asn polymorphism in the OPG gene is associated with L2–4 BMD in postmenopausal women. The Lys-allele is associated with lower BMD and an increased risk for osteoporosis.

Keywords

Bone mineral density Gene Osteoprotegerin Single nucleotide polymorphism 

References

  1. 1.
    Giguere Y, Rousseau F (2000) The genetics of osteoporosis: “complexities and difficulties.” Clin Genet 57:161–169Google Scholar
  2. 2.
    Morrison NA, Qi JC, Tokita A, et al (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287CrossRefPubMedGoogle Scholar
  3. 3.
    Uitterlinden AG, Pols HAP, Burger H, et al (1996) A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res 11:1242–1248Google Scholar
  4. 4.
    Kobayashi S, Inoue S, Hosoi T, et al (1996) Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res 11:306–311PubMedGoogle Scholar
  5. 5.
    van Meurs JB, Schuit SC, Weel AE, et al (2003) Association of 5’ estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Hum Mol Genet 12:1745–1754CrossRefGoogle Scholar
  6. 6.
    Grant SFA, Reid DM, Blake G, et al (1996) Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type Iα1 gene. Nat Genet 14:203–205PubMedGoogle Scholar
  7. 7.
    Uitterlinden AG, Burger H, Huang Q, et al (1998) Relation of alleles of the collagen type Iα1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 338:1016–1021CrossRefPubMedGoogle Scholar
  8. 8.
    Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137CrossRefPubMedGoogle Scholar
  9. 9.
    Lacey DL, Timms E, Tan H-L, et al (1998) Osteoprotegerin (OPG) ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176CrossRefPubMedGoogle Scholar
  10. 10.
    Anderson MA, Maraskovsky E, Billingsley WL, et al (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–179CrossRefPubMedGoogle Scholar
  11. 11.
    Simonet WS, Lacey DL, Dunstan CR, et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319CrossRefPubMedGoogle Scholar
  12. 12.
    Bucay N, Sarosi I, Dunstan CR, et al (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268PubMedGoogle Scholar
  13. 13.
    Mizuno A, Amizuka N, Irie K, et al (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615CrossRefPubMedGoogle Scholar
  14. 14.
    Geneva:WHO (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. WHO Technical Report Series, no. 843Google Scholar
  15. 15.
    Morinaga T, Nakagawa N, Yasuda H, et al (1998) Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor. Eur J Biochem 254:685–691Google Scholar
  16. 16.
    Langdahl B, Carstens M, Stenkjaer L, et al (2002) Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res 17:1245–1255PubMedGoogle Scholar
  17. 17.
    Ohmori H, Makita Y, Funamizu M, et al (2002) Linkage and association analyses of the osteoprotegerin gene locus with human osteoporosis. J Hum Genet 47:400–406Google Scholar
  18. 18.
    Wynne F, Drummond F, O’Sullivan K, et al (2002) Investigation of the genetic influence of the OPG, VDR(Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population. Calcif Tissue Int 71:26–35Google Scholar
  19. 19.
    Nakajima T, Cheng T, Rohrwasser A, et al (1999) Functional analysis of a mutation occurring between the two in-frame AUG codons of human angiotensinogen. J Biol Chem 274:35749–35755Google Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2005

Authors and Affiliations

  • Hong-yan Zhao
    • 1
    • 1
  • Jian-min Liu
    • 1
  • Guang Ning
    • 1
  • Yong-ju Zhao
    • 1
    • 1
  • Lian-zhen Zhang
    • 1
  • Li-hao Sun
    • 1
  • Man-yin Xu
    • 1
  • A. G. Uitterlinden
    • 2
  • Jia-lun Chen
    • 1
  1. 1.Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Second Medical UniversityShanghaiChina
  2. 2.Genetic Laboratory, Department of Internal MedicineErasmus MCRotterdamThe Netherlands

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