The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.
BACKGROUND
Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear.


OBJECTIVE
To evaluate the relation between VDR polymorphisms, BMD, and fractures.


METHODS
Prospective multicenter large-scale association study.


METHODS
The Genetic Markers for Osteoporosis consortium, involving 9 European research teams.


METHODS
26,242 participants (18,405 women).


METHODS
Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures.


RESULTS
Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model).


CONCLUSIONS
The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis.


CONCLUSIONS
The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.
Uitterlinden
André G
AG
Erasmus MC, Rotterdam, The Netherlands.
Ralston
Stuart H
SH
Brandi
Maria Luisa
ML
Carey
Alisoun H
AH
Grinberg
Daniel
D
Langdahl
Bente L
BL
Lips
Paul
P
Lorenc
Roman
R
Obermayer-Pietsch
Barbara
B
Reeve
Jonathan
J
Reid
David M
DM
Amedei
Antonietta
A
Amidei
Antonietta
A
Bassiti
Amelia
A
Bustamante
Mariona
M
Husted
Lise Bjerre
LB
Diez-Perez
Adolfo
A
Dobnig
Harald
H
Dunning
Alison M
AM
Enjuanes
Anna
A
Fahrleitner-Pammer
Astrid
A
Fang
Yue
Y
Karczmarewicz
Elzbieta
E
Kruk
Marcin
M
van Leeuwen
Johannes P T M
JP
Mavilia
Carmelo
C
van Meurs
Joyce B J
JB
Mangion
Jon
J
McGuigan
Fiona E A
FE
Pols
Huibert A P
HA
Renner
Wilfried
W
Rivadeneira
Fernando
F
van Schoor
Natasja M
NM
Scollen
Serena
S
Sherlock
Rachael E
RE
Ioannidis
John P A
JP
D000328:Adult; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D000071616:CDX2 Transcription Factor; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D050723:Fractures, Bone / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018167:Receptors, Calcitriol / Q000235:genetics*
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D018167:Receptors, Calcitriol; C053864:endodeoxyribonuclease BsmI; C035042:endodeoxyribonuclease FokI; D015252:Deoxyribonucleases, Type II Site-Specific; C038485:GGGCCC-specific type II deoxyribonucleases; C027046:TCGA-specific type II deoxyribonucleases