Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of common variants in CNR2 gene for bone mineral density and osteoporosis susceptibility in postmenopausal women of Han Chinese

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Postmenopausal osteoporosis is a major health problem with important genetic factors in postmenopausal women. We thoroughly evaluated the relationship of CNR2 polymorphisms with osteoporosis in a cohort of 1032 osteoporosis patients and 2089 healthy controls from Han Chinese postmenopausal women. Statistically significant differences, depending on different genotypes, were presented.

Introduction

Osteoporosis is a major health problem in postmenopausal women, which is a multifactorial disease in which genetic determinants are modulated by hormonal, environmental, and nutritional factors. An important clinical risk factor in the pathogenesis of osteoporosis is the presence of genetic polymorphism in susceptibility genes. The aim of our study was to investigate whether CNR2 gene, which attributes to osteoporosis susceptibility in some populations, is associated with bone mineral density (BMD) or osteoporosis in Han Chinese postmenopausal women.

Methods

We examine 39 SNPs covering the region of CNR2 gene in 3121 Han Chinese postmenopausal women, consisting of 1032 osteoporosis patients and 2089 healthy controls, to evaluate the association with BMD and osteoporosis.

Results

We found that rs4237 and rs2501431 were significantly associated with BMD and osteoporosis (corrected p = 0.020085 and 0.017199) in our sample, and the TT genotype of rs2501431 and the AA genotype of rs4237 had lower lumbar spine BMD and femoral neck BMD compared with the other genotypes. Additionally, analyses by haplotypes indicated that two haplotype blocks, containing rs4237 and rs2501431 respectively, in the CNR2 gene significantly associated with BMD and osteoporosis (both global permutation p < 0.001), and a risk haplotype (ATTT) in the block of rs3003336-rs2501431-rs2502992-rs2501432 had almost 4-fold increase in the cases.

Conclusions

Our results provide further supportive evidence for an important role of CNR2 gene in the etiology of osteoporosis and suggest that it may be a genetic risk factor for BMD and osteoporosis in Han Chinese postmenopausal women.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141

    Article  CAS  PubMed  Google Scholar 

  2. Gammage KL, Gasparotto J, Mack DE, Klentrou P (2012) Gender differences in osteoporosis health beliefs and knowledge and their relation to vigorous physical activity in university students. J Am Coll Heal 60:58–64

    Article  Google Scholar 

  3. Geng L, Yao Z, Yang H, Luo J, Han L, Lu Q (2007) Association of CA repeat polymorphism in estrogen receptor β gene with postmenopausal osteoporosis in Chinese. J Genet Genomics 34:868–876

    Article  CAS  PubMed  Google Scholar 

  4. Garcia-Unzueta M, Riancho J, Zarrabeitia M, Sanudo C, Berja A, Valero C, Pesquera C, Paule B, González-Macías J, Amado J (2008) Association of the 163A/G and 1181G/C osteoprotegerin polymorphism with bone mineral density. Horm Metab Res 40:219–224

    Article  CAS  PubMed  Google Scholar 

  5. Li Y, Xi B, Li K, Wang C (2012) Association between vitamin D receptor gene polymorphisms and bone mineral density in Chinese women. Mol Biol Rep 39:5709–5717

    Article  CAS  PubMed  Google Scholar 

  6. Woo J, Kim Y, Lee C (2012) Heterogeneous genetic associations of nucleotide sequence variants with bone mineral density by gender. Mol Biol Rep 39:2259–2265

    Article  CAS  PubMed  Google Scholar 

  7. Duncan EL, Brown MA (2010) Genetic determinants of bone density and fracture risk—state of the art and future directions. J Clin Endocrinol Metab 95:2576–2587

    Article  CAS  PubMed  Google Scholar 

  8. Albagha OM, Ralston SH (2006) Genetics and osteoporosis. Rheum Dis Clin N Am 32:659–680

    Article  Google Scholar 

  9. Hosoi T (2010) Genetic aspects of osteoporosis. J Bone Miner Metab 28:601–607

    Article  CAS  PubMed  Google Scholar 

  10. Ralston SH (2010) Genetics of osteoporosis. Ann N Y Acad Sci 1192:181–189

    Article  CAS  PubMed  Google Scholar 

  11. Ferrari S (2008) Human genetics of osteoporosis. Best Pract Res Clin Endocrinol Metab 22:723–735

    Article  CAS  PubMed  Google Scholar 

  12. Cheung CL, Xiao SM, Kung AW (2010) Genetic epidemiology of age-related osteoporosis and its clinical applications. Nat Rev Rheumatol 6:507–517

    Article  PubMed  Google Scholar 

  13. Özbaş H, Onrat ST, Özdamar K (2012) Genetic and environmental factors in human osteoporosis. Mol Biol Rep 39:11289–11296

    Article  PubMed  Google Scholar 

  14. Guan F, Zhang C, Wei S, Zhang H, Gong X, Feng J, Gao C, Su R, Yang H, Li S (2012) Association of PDE4B polymorphisms and schizophrenia in Northwestern Han Chinese. Hum Genet 131:1047–1056

    Article  CAS  PubMed  Google Scholar 

  15. Guan F, Wei S, Feng J, Zhang C, Xing B, Zhang H, Gao C, Yang H, Li S (2012) Association study of a new schizophrenia susceptibility locus of 10q24.32–33 in a Han Chinese population. Schizophr Res 138:63–68

    Article  PubMed  Google Scholar 

  16. Guan F, Wei S, Zhang C, Zhang H, Zhang B, Xing B, Feng Z, Gao C, Liu X, Li S (2013) A population-based association study of 2q32.3 and 8q21.3 loci with schizophrenia in Han Chinese. J Psychiatr Res 47:712–717

    Article  PubMed  Google Scholar 

  17. Guan F, Zhang B, Yan T, Li L, Liu F, Li T, Feng Z, Zhang B, Liu X, Li S (2014) MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. Schizophr Res 152:97–104

    Article  PubMed  Google Scholar 

  18. Zmuda JM, Cauley JA, Ferrell RE (1999) Recent progress in understanding the genetic susceptibility to osteoporosis. Genet Epidemiol 16:356–367

    Article  CAS  PubMed  Google Scholar 

  19. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH (1996) Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I α 1 gene. Nat Genet 14:203–205

    Article  CAS  PubMed  Google Scholar 

  20. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    Article  CAS  PubMed  Google Scholar 

  21. Devoto M, Shimoya K, Caminis J, Ott J, Tenenhouse A, Whyte M, Sereda L, Hall S, Considine E, Williams C (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

    Article  CAS  PubMed  Google Scholar 

  22. Devoto M, Specchia C, Li HH, Caminis J, Tenenhouse A, Rodriguez H, Spotila LD (2001) Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36. Hum Mol Genet 10:2447–2452

    Article  CAS  PubMed  Google Scholar 

  23. Devoto M, Spotila LD, Stabley DL, Wharton GN, Rydbeck H, Korkko J, Kosich R, Prockop D, Tenenhouse A, Sol-Church K (2005) Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density. Eur J Hum Genet 13:781–788

    Article  CAS  PubMed  Google Scholar 

  24. Karsak M, Ofek O, Fogel M, Wright K, Tam J, Gabet Y, Birenboim R, Attar-Namdar M, Muller R, Cohen-Solal M (2004) The cannabinoid CB2 receptor: a potential target for the diagnosis and treatment of osteoporosis. J Bone Miner Res 19:S383

    Google Scholar 

  25. Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E, Bab I, Kubisch C (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet 14:3389–3396

    Article  CAS  PubMed  Google Scholar 

  26. Yamada Y, Ando F, Shimokata H (2007) Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men. Int J Mol Med 19:791–801

    CAS  PubMed  Google Scholar 

  27. Karsak M, Malkin I, Toliat MR, Kubisch C, Nürnberg P, Zimmer A, Livshits G (2009) The cannabinoid receptor type 2 (CNR2) gene is associated with hand bone strength phenotypes in an ethnically homogeneous family sample. Hum Genet 126:629–636

    Article  CAS  PubMed  Google Scholar 

  28. Huang QY, Li GH, Kung AW (2009) Multiple osteoporosis susceptibility genes on chromosome 1p36 in Chinese. Bone 44:984–988

    Article  CAS  PubMed  Google Scholar 

  29. Wang C, Zhang Z, Zhang H, He JW, Gu JM, Hu WW, Hu YQ, Li M, Liu YJ, Fu WZ (2012) Susceptibility genes for osteoporotic fracture in postmenopausal Chinese women. J Bone Miner Res 27:2582–2591

    Article  CAS  PubMed  Google Scholar 

  30. Woo JH, Kim H, Kim JH, Kim JG (2014) Cannabinoid receptor gene polymorphisms and bone mineral density in Korean postmenopausal women. Menopause. doi:10.1097/gme.0000000000000339

    PubMed  Google Scholar 

  31. Chen J, Zheng H, Bei J-X, Sun L, W-h J, Li T, Zhang F, Seielstad M, Zeng Y-X, Zhang X (2009) Genetic structure of the Han Chinese population revealed by genome-wide SNP variation. Am J Hum Genet 85:775–785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Idris AI, Ralston SH (2012) Role of cannabinoids in the regulation of bone remodeling. Front Endocrinol 3:136

    Google Scholar 

  33. Bab I, Zimmer A (2008) Cannabinoid receptors and the regulation of bone mass. Br J Pharmacol 153:182–188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A 103:696–701

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Sophocleous A, Landao-Bassonga E, Van’t Hof RJ, Idris AI, Ralston SH (2011) The type 2 cannabinoid receptor regulates bone mass and ovariectomy-induced bone loss by affecting osteoblast differentiation and bone formation. Endocrinology 152:2141–2149

    Article  CAS  PubMed  Google Scholar 

  36. Ofek O, Attar-Namdar M, Kram V, Dvir-Ginzberg M, Mechoulam R, Zimmer A, Frenkel B, Shohami E, Bab I (2011) CB2 cannabinoid receptor targets mitogenic Gi protein-cyclin D1 axis in osteoblasts. J Bone Miner Res 26:308–316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Carrasquer A, Nebane NM, Williams WM, Song Z-H (2010) Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics 20:157–166

    Article  CAS  PubMed  Google Scholar 

  38. Sipe JC, Arbour N, Gerber A, Beutler E (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol 78:231–238

    Article  CAS  PubMed  Google Scholar 

  39. Sophocleous A, Idris AI, Ralston SH (2014) Genetic background modifies the effects of type 2 cannabinoid receptor deficiency on bone mass and bone turnover. Calcif Tissue Int 94:259–268

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Chen Zhang and Miao Li conceived and designed the experiments. Jun Ma performed the experiments. Chen Zhang and Gang Chen analyzed the data. Dongke Fu and Lu Li contributed the reagents/materials/analysis tools. Chen Zhang wrote the paper. This research was totally supported by the National Natural Science Foundation of China (no. 81301562). The funding sources had no role in the design of this study, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the paper for publication.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. The First Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, 157 Xiwu road, Xi’an, 710061, China

    C. Zhang & J. Ma

  2. College of Medicine & Forensics, Xi’an Jiaotong University, 76 West Yanta road, Xi’an, 710061, China

    G. Chen, D. Fu & L. Li

  3. Department of Ultrasound, the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, 157 Xiwu road, Xi’an, 710061, China

    M. Li

Authors
  1. C. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Li.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 160 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, C., Ma, J., Chen, G. et al. Evaluation of common variants in CNR2 gene for bone mineral density and osteoporosis susceptibility in postmenopausal women of Han Chinese. Osteoporos Int 26, 2803–2810 (2015). https://doi.org/10.1007/s00198-015-3195-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-015-3195-x

Keywords

Search

Navigation