title: 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.
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.
  
  
  BACKGROUND
  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.
  
  
  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: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Elin.Grundberg@medsci.uu.se
authors: Elin
authors: E
authors: Grundberg
authors: Edith M C
authors: EM
authors: Lau
authors: Tomi
authors: T
authors: Pastinen
authors: Andreas
authors: A
authors: Kindmark
authors: Olof
authors: O
authors: Nilsson
authors: Osten
authors: O
authors: Ljunggren
authors: Dan
authors: D
authors: Mellström
authors: Eric
authors: E
authors: Orwoll
authors: Inga
authors: I
authors: Redlund-Johnell
authors: Anna
authors: A
authors: Holmberg
authors: Scott
authors: S
authors: Gurd
authors: Ping Chung
authors: PC
authors: Leung
authors: Timothy
authors: T
authors: Kwok
authors: Claes
authors: C
authors: Ohlsson
authors: Hans
authors: H
authors: Mallmin
authors: Helena
authors: H
authors: Brändström
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance; D044466:Asian People; D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D005269:Femur / Q000166:cytology / Q000378:metabolism; D005272:Femur Neck / Q000737:chemistry / Q000378:metabolism; D050723:Fractures, Bone / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006723:Hong Kong; D006801:Humans; D008159:Lumbar Vertebrae / Q000737:chemistry / Q000378:metabolism; D008297:Male; D010024:Osteoporosis / Q000235:genetics; D010384:Pelvic Bones / Q000737:chemistry / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D016103:Spinal Fractures / Q000235:genetics; D013548:Sweden
chemical_list: D020413:3' Untranslated Regions; D018167:Receptors, Calcitriol