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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. 2007 Jun; 22(6):832-40.JB

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.

Authors+Show Affiliations

Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Elin.Grundberg@medsci.uu.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17371163

Citation

Grundberg, Elin, et al. "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 : the Official Journal of the American Society for Bone and Mineral Research, vol. 22, no. 6, 2007, pp. 832-40.
Grundberg E, Lau EM, Pastinen T, et al. 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. 2007;22(6):832-40.
Grundberg, E., Lau, E. M., Pastinen, T., Kindmark, A., Nilsson, O., Ljunggren, O., Mellström, D., Orwoll, E., Redlund-Johnell, I., Holmberg, A., Gurd, S., Leung, P. C., 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 : the Official Journal of the American Society for Bone and Mineral Research, 22(6), 832-40.
Grundberg E, et al. 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. 2007;22(6):832-40. PubMed PMID: 17371163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Grundberg,Elin, AU - Lau,Edith M C, AU - Pastinen,Tomi, AU - Kindmark,Andreas, AU - Nilsson,Olof, AU - Ljunggren,Osten, AU - Mellström,Dan, AU - Orwoll,Eric, AU - Redlund-Johnell,Inga, AU - Holmberg,Anna, AU - Gurd,Scott, AU - Leung,Ping Chung, AU - Kwok,Timothy, AU - Ohlsson,Claes, AU - Mallmin,Hans, AU - Brändström,Helena, PY - 2007/3/21/pubmed PY - 2007/8/30/medline PY - 2007/3/21/entrez SP - 832 EP - 40 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 22 IS - 6 N2 - UNLABELLED: 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. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/17371163/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_ L2 - https://doi.org/10.1359/jbmr.070317 DB - PRIME DP - Unbound Medicine ER -