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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.

Journal article
Authors Elin Grundberg
Edith M C Lau
Tomi Pastinen
Andreas Kindmark
Olof Nilsson
Osten Ljunggren
Dan Mellström
Eric Orwoll
Inga Redlund-Johnell
Anna Holmberg
Scott Gurd
Ping Chung Leung
Timothy Kwok
Claes Ohlsson
Hans Mallmin
Helena Brändström
Published in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume 22
Issue 6
Pages 832-40
ISSN 0884-0431
Publication year 2007
Published at Institute of Medicine, School of Public Health and Community Medicine
Institute of Medicine, Department of Internal Medicine
Pages 832-40
Language en
Keywords 3' Untranslated Regions, genetics, Aged, Aged, 80 and over, Allelic Imbalance, Asian Continental Ancestry Group, Bone Density, genetics, Bone and Bones, cytology, metabolism, Femur, cytology, metabolism, Femur Neck, chemistry, metabolism, Fractures, Bone, genetics, Gene Frequency, Haplotypes, Heterozygote, Homozygote, Hong Kong, Humans, Lumbar Vertebrae, chemistry, metabolism, Male, Osteoporosis, genetics, Pelvic Bones, chemistry, metabolism, Polymorphism, Single Nucleotide, Receptors, Calcitriol, genetics, Risk Factors, Spinal Fractures, genetics, Sweden
Subject categories Medical and Health Sciences


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.

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