Skip to main content

Advertisement

SpringerLink
Log in

Vitamin D receptor (VDR) gene polymorphism influences the risk of osteoporosis in postmenopausal women of Northwest India

  • Original Article
  • Published:
Archives of Osteoporosis Aims and scope Submit manuscript

Abstract

Summary

The influence of VDR gene for the risk of osteoporosis has remained inconclusive. VDR gene polymorphism in relation to BMD in postmenopausal women of Northwest India revealed a susceptibility haplotype AGT. Possession of this haplotype exacerbates the risk of osteoporosis by 2.8 times, which manifests in recessive mode of inheritance.

Purpose

The purpose of this study is to understand the influence of coordinated effect of various single nucleotide polymorphisms (SNPs) within vitamin D receptor (VDR) gene for the risk of osteoporosis, which has remained undefined so far.

Methods

Four pertinent SNPs of VDR gene, i.e., rs2228570, rs1544410, rs17879735, and rs731236 were examined with polymerase chain reaction–restriction fragment length polymorphism in dual energy X-ray absorptiometry verified 188 osteoporotics, 115 osteopenics, and 147 normal postmenopausal women of Northwest India.

Results

Minor allele ‘T’ of rs2228570 showed significant influence for the risk of osteoporosis (OR 1.60, 95%CI 1.16–2.20, P = 0.004) and also in dominant (OR 2.32, 95%CI 1.47–3.64, P = 0.0006) and additive model (OR 2.41, 95%CI 1.49–3.87, P = 0.0006) after Bonferroni correction. Minor allele (T) of rs2228570 showed an allele dose effect with BMD of L1-L4 (P = 0.009) and FN (P = 0.036). Disease association analysis exposed a susceptibility haplotype AGT which influences the risk of osteopenia (OR 2.04, 95%CI 1.03–4.08, P = 0.036) and osteoporosis (OR 2.90, 95%CI 1.61–5.38, P = 0.00005) after adjusting the effects of age, BMI and years since menopause. This haplotype is significantly associated with BMDs at lumbar spine (P = 0.0001) and femoral neck (P = 0.016).

Conclusion

In-depth analysis of this haplotype with other methods of Wald statistics and Akaike information criterion confirmed that carriers of each unit of this haplotype AGT increases the risk of osteoporosis by a factor of 2.80 ± 0.34 (β ± SE) which manifests (P = 0.1 × 10−6) in its recessive mode of inheritance.

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

Similar content being viewed by others

References

  1. Kelly PJ, Morrison NA, Sambrook PN, Nguyen TV, Eisman JA (1995) Genetic influences on bone turnover, bone density and fracture. Eur J Endocrinol 133:265–271

    Article  CAS  PubMed  Google Scholar 

  2. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults. A twin study. J Clin Invest 80:706–710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Guéguen R, Jouanny P, Guillemin F, Kuntz C, Pourel J, Siest G (1995) Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Miner Res 10:2017–2022

    Article  PubMed  Google Scholar 

  4. Yoshida T, Stern PH (2012) How vitamin D works on bone. Endocrinol Metab Clin N Am 41:557–569

    Article  CAS  Google Scholar 

  5. Carlberg C, Molnar F (2012) Current status of vitamin D signaling and its therapeutic applications. Curr Top Med Chem 12:528–547

    Article  CAS  PubMed  Google Scholar 

  6. Turner AG, Anderson PH, Morris HA (2012) Vitamin D and bone health. Scand J Clin Lab Inv Suppl 243:65–72

    Google Scholar 

  7. Bouillon R, Okamura WH, Norman AW (1995) Structure-function relationships in the vitamin D endocrine system. Endocr Rev 16:200–257

    CAS  PubMed  Google Scholar 

  8. Miyamoto K, Kesterson RA, Yamamoto H et al (1997) Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol 11:1165–1179

    Article  CAS  PubMed  Google Scholar 

  9. Taymans SE, Pack S, Pak E et al (1999) The human vitamin D receptor gene (VDR) is localized to region 12cen-q12 by fluorescent in situ hybridization and radiation hybrid mapping: genetic and physical VDR map. J Bone Miner Res 14:1163–1166

    Article  CAS  PubMed  Google Scholar 

  10. Morrison NA, Qi JC, Tokita A et al (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287

    Article  CAS  PubMed  Google Scholar 

  11. Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF, Gilsanz V (1997) Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 337:77–82

    Article  CAS  PubMed  Google Scholar 

  12. Kurabayashi T, Tomita M, Matsushita H et al (1999) Association of vitamin D and estrogen receptor gene polymorphism with the effect of hormone replacement therapy on bone mineral density in Japanese women. Am J Obstet Gynecol 180:1115–1120

    Article  CAS  PubMed  Google Scholar 

  13. Mencej-Bedrac S, Prezelj J, Kocjan T et al (2009) The combinations of polymorphisms in vitamin D receptor, osteoprotegerin and tumour necrosis factor superfamily member 11 genes are associated with bone mineral density. J Mol Endocrinol 42:239–247

    Article  CAS  PubMed  Google Scholar 

  14. Gong G, Stern HS, Cheng SC et al (1999) The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 9:55–64

    Article  CAS  PubMed  Google Scholar 

  15. Thakkinstian A, D'Este C, Eisman J, Nguyen T, Attia J (2004) Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study. J Bone Miner Res 19:419–428

    Article  CAS  PubMed  Google Scholar 

  16. Thakkinstian A, D'Este C, Attia J (2004) Haplotype analysis of VDR gene polymorphisms: a meta-analysis. Osteoporos Int 15:729–734

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Fang Y, Rivadeneira F, van Meurs JB, Pols HA, Ioannidis JP, Uitterlinden AG (2006) Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: a meta-analysis. Bone 39:938–945

    Article  CAS  PubMed  Google Scholar 

  19. Uitterlinden AG, Ralston SH, Brandi ML et al (2006) The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med 145:255–264

    Article  CAS  PubMed  Google Scholar 

  20. Zintzaras E, Rodopoulou P, Koukoulis GN (2006) BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis. Dis Markers 22:317–326

    Article  CAS  PubMed  Google Scholar 

  21. Qin G, Dong Z, Zeng P, Liu M, Liao X (2013) Association of vitamin D receptor BsmI gene polymorphism with risk of osteoporosis: a meta-analysis of 41 studies. Mol Biol Rep 40:497–506

    Article  CAS  PubMed  Google Scholar 

  22. Krishna U, Mehta RU (2000) Osteoporosis—incidence and implications. J Obstet Gynecol India 50:150–155

    Google Scholar 

  23. Johnell O, Gullberg B, Allander E et al (1992) The apparent incidence of hip fracture in Europe: a study of national register sources. MEDOS Study Group. Osteoporos Int 2:298–302

    Article  CAS  PubMed  Google Scholar 

  24. Gupta A (1998) Osteoporosis in India-the nutritional hypothesis. In: Metabolic bone disorders. Indian Society for Bone and Mineral Research, Eds: Mithal A, Rao DS, Zaidi M. 115–132

  25. Cooper C, Campion G, Melton LJ 3rd (1992) Hip fractures in the elderly: a world-wide projection. Osteoporos Int 2:285–289

    Article  CAS  PubMed  Google Scholar 

  26. Singh M, Singh P, Singh S, Juneja PK, Kaur T (2010) A susceptible haplotype within APOE gene influences BMD and intensifies the osteoporosis risk in postmenopausal women of Northwest India. Maturitas 67:239–244

    Article  CAS  PubMed  Google Scholar 

  27. World Health Organisation (WHO) (1993) Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94:646–650

    Article  Google Scholar 

  28. Long JR, Zhao LJ, Liu PY et al (2004) Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes. BMC Genet 24:5–11

    Google Scholar 

  29. Sasieni PD (1997) From genotypes to genes: doubling the sample size. Biometrics 53:1253–1261

    Article  CAS  PubMed  Google Scholar 

  30. Excoffier L, Laval G, Schneider S (2007) Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50

    PubMed Central  PubMed  Google Scholar 

  31. Akaike H (1987) Factor analysis and AIC. Psychometrika 52:317–332

    Article  Google Scholar 

  32. Menashe I, Rosenberg PS, Chen BE (2008) PGA: power calculator for case–control genetic association analyses. BMC Genet 9:36

    Article  PubMed Central  PubMed  Google Scholar 

  33. Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004

    Article  CAS  PubMed  Google Scholar 

  34. Mitra S, Desai M, Ikram Khatkhatay M (2006) Vitamin D receptor gene polymorphisms and bone mineral density in postmenopausal Indian women. Maturitas 55:27–35

    Article  CAS  PubMed  Google Scholar 

  35. Gennari L, Becherini L, Masi L et al (1998) Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density. J Clin Endocrinol Metab 83:939–944

    Article  CAS  PubMed  Google Scholar 

  36. Singh M, Singh P, Juneja PK, Singh S, Kaur T (2011) SNP-SNP interactions within APOE gene influence plasma lipids in postmenopausal osteoporosis. Rheumatol Int 31:421–423

    Article  PubMed  Google Scholar 

  37. Rubin LA, Hawker GA, Peltekova VD, Fielding LJ, Ridout R, Cole DE (1999) Determinants of peak bone mass: clinical and genetic analyses in a young female Canadian cohort. J Bone Miner Res 14:633–643

    Article  CAS  PubMed  Google Scholar 

  38. Douroudis K, Tarassi K, Ioannidis G et al (2003) Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin. Maturitas 45:191–197

    Article  CAS  PubMed  Google Scholar 

  39. Colin EM, Uitterlinden AG, Meurs JB et al (2003) Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk. J Clin Endocrinol Metab 88:3777–3784

    Article  CAS  PubMed  Google Scholar 

  40. Uitterlinden AG, Weel AE, Burger H et al (2001) Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture. J Bone Miner Res 16:379–385

    Article  CAS  PubMed  Google Scholar 

  41. Grundberg E, Lau EM, Pastinen T, Kindmark A et al (2007) Vitamin D receptor 3′ haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the MrOS Study in Sweden and Hong Kong. J Bone Miner Res 22:832–840

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The financial support of the DST project (SR/WOS-A/LS-225/2007) to MS is highly acknowledged.

Role of Funding Source

The present study is a part of the major research project (SR/WOS-A/LS-225/2007) funded by department of Science and Technology (DST), New Delhi to Dr. Monica Singh. The funding agency had no role in the design, collection, analysis and interpretation of data; in the writing of the report and in the decision to submit the paper for publication.

Conflicts of Interest

None.

Author information

Authors and Affiliations

  1. Molecular Genetics Laboratory, Department of Human Genetics, Punjabi University, Patiala, Punjab, India

    Monica Singh & Puneetpal Singh

  2. Aggarwal Orthopedic Hospital, Ludhiana, Punjab, India

    Surinder Singh & Pawan Kumar Juneja

  3. Amrit Sagar Hospital, Ferozepur, Punjab, India

    Taranpal Kaur

  4. Department of Human Genetics, Punjabi University, Patiala, 147002, Punjab, India

    Puneetpal Singh

Authors
  1. Monica Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Puneetpal Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Surinder Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pawan Kumar Juneja
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Taranpal Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Puneetpal Singh.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 47 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, M., Singh, P., Singh, S. et al. Vitamin D receptor (VDR) gene polymorphism influences the risk of osteoporosis in postmenopausal women of Northwest India. Arch Osteoporos 8, 147 (2013). https://doi.org/10.1007/s11657-013-0147-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11657-013-0147-y

Keywords

Search

Navigation