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.
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.
Grundberg
Elin
E
Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Elin.Grundberg@medsci.uu.se
Lau
Edith M C
EM
Pastinen
Tomi
T
Kindmark
Andreas
A
Nilsson
Olof
O
Ljunggren
Osten
O
Mellström
Dan
D
Orwoll
Eric
E
Redlund-Johnell
Inga
I
Holmberg
Anna
A
Gurd
Scott
S
Leung
Ping Chung
PC
Kwok
Timothy
T
Ohlsson
Claes
C
Mallmin
Hans
H
Brändström
Helena
H
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
D020413:3' Untranslated Regions; D018167:Receptors, Calcitriol