Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes.
BACKGROUND
Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results.


OBJECTIVE
To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI [dbSNP: rs9340799] and PvuII [dbSNP: rs2234693] and promoter TA repeats microsatellite) and haplotypes thereof are associated with BMD and fractures.


METHODS
Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers.


METHODS
BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype.


RESULTS
No between-center heterogeneity was observed for any outcome in any genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically significant effect on BMD in adjusted or unadjusted analyses, and estimated differences between genetic contrasts were 0.01 g/cm2 or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% CI, 0.71-0.93]; P = .002) and vertebral fractures by 35% (odds ratio, 0.65 [95% CI, 0.49-0.87]; P = .003). Effects on fractures were independent of BMD and unaltered in adjusted analyses. No significant effects on fracture risk were seen for PvuII and TA repeats.


CONCLUSIONS
ESR1 is a susceptibility gene for fractures, and XbaI determines fracture risk by mechanisms independent of BMD. Our study demonstrates the value of adequately powered studies with standardized genotyping and clinical outcomes in defining effects of common genetic variants on complex diseases.
Ioannidis
John P A
JP
Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. jioannid@cc.uoi.gr
Ralston
Stuart H
SH
Bennett
Simon T
ST
Brandi
Maria Luisa
ML
Grinberg
Daniel
D
Karassa
Fotini B
FB
Langdahl
Bente
B
van Meurs
Joyce B J
JB
Mosekilde
Leif
L
Scollen
Serena
S
Albagha
Omar M E
OM
Bustamante
Mariona
M
Carey
Alisoun H
AH
Dunning
Alison M
AM
Enjuanes
Anna
A
van Leeuwen
Johannes P T M
JP
Mavilia
Carmelo
C
Masi
Laura
L
McGuigan
Fiona E A
FE
Nogues
Xavier
X
Pols
Huibert A P
HA
Reid
David M
DM
Schuit
Stephanie C E
SC
Sherlock
Rachael E
RE
Uitterlinden
André G
AG
D000368:Aged; D015519:Bone Density / Q000235:genetics*; D047628:Estrogen Receptor alpha; D005260:Female; D005272:Femur Neck; D050723:Fractures, Bone / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D015201:Meta-Analysis as Topic; D018895:Microsatellite Repeats; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D011960:Receptors, Estrogen / Q000235:genetics*; D012306:Risk
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen