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

Elin Grundberg, Edith M.C. Lau, Tomi Pastinen, Andreas Kindmark, Olof Nilsson, Östen Ljunggren, Dan Mellström, Eric Orwoll, Inga Redlund-Johnell, Anna Holmberg, Scott Gurd, Chung Leung Ping, Timothy Kwok, Claes Ohlsson, Hans Mallmin, Helena Brändström

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The VDR is a prime candidate gene for osteoporosis. Here, we studied three common VDR haplotypes in relation to bone phenotypes in 5014 participants of the global MrOS Study. We also studied the relative expression of the haplotypes in human bone cells. One haplotype was associated with increased fracture risk and differently expressed in primary human bone cells. Introduction: Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of BMD is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. Materials and Methods: Here, we reconstructed common haplotypes in the VDR 3′ untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in elderly men from Sweden (n = 3014) and Hong Kong (n = 2000), all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, we studied allele-specific expressions of the different VDR 3′ UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples. Results: Three major haplotypes were reconstructed and in agreement with the previously well-defined baT, BAt, and bAT haplotypes, herein denoted Hap1, Hap2, and Hap3. The Hap1 haplotype was independently associated with increased risk of vertebral fractures in Swedish men (OR, 1.655; 95% CI, 1.146-2.391; p < 0.01) and with lower lumbar spine BMD in elderly men from Sweden (p < 0.01) and Hong Kong (p < 0.05). The VDR gene was also shown to exhibit a 3′ UTR haplotype dependent allelic imbalance, indicating that the VDR Hap1 allele was overexpressed in human trabecular bone samples. Conclusions: The results indicate that the relatively overexpressed VDR Hap1 haplotype could be considered a risk allele for osteoporosis regardless of ethnicity.

Original languageEnglish (US)
Pages (from-to)832-840
Number of pages9
JournalJournal of Bone and Mineral Research
Volume22
Issue number6
DOIs
StatePublished - Jun 2007

Keywords

  • 3′ untranslated region
  • Allelic imbalance
  • BMD
  • Fracture risk
  • Haplotypes
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Grundberg, E., Lau, E. M. C., Pastinen, T., Kindmark, A., Nilsson, O., Ljunggren, Ö., Mellström, D., Orwoll, E., Redlund-Johnell, I., Holmberg, A., Gurd, S., Ping, C. L., Kwok, T., Ohlsson, C., Mallmin, H., & Brändström, H. (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. Journal of Bone and Mineral Research, 22(6), 832-840. https://doi.org/10.1359/jbmr.070317