Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes

CONTEXT Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor α (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....

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Published in:JAMA : the journal of the American Medical Association 2004-11, Vol.292 (17), p.2105-2114
Main Authors: Ioannidis, John P. A, Ralston, Stuart H, Bennett, Simon T, Brandi, Maria Luisa, Grinberg, Daniel, Karassa, Fotini B, Langdahl, Bente, van Meurs, Joyce B. J, Mosekilde, Leif, Scollen, Serena, Albagha, Omar M. E, Bustamante, Mariona, Carey, Alisoun H, Dunning, Alison M, Enjuanes, Anna, van Leeuwen, Johannes P. T. M, Mavilia, Carmelo, Masi, Laura, McGuigan, Fiona E. A, Nogues, Xavier, Pols, Huibert A. P, Reid, David M, Schuit, Stephanie C. E, Sherlock, Rachael E, Uitterlinden, André G, GENOMOS Study, for the
Format: Article
Language:English
Subjects:
Aged
Biological and medical sciences
Bone Density - genetics
Bones
Diseases of the osteoarticular system
Estrogen Receptor alpha
Female
Femur Neck
Fractures
Fractures, Bone - epidemiology
Fractures, Bone - genetics
General aspects
Genetic Predisposition to Disease
Genetics
Genotype
Haplotypes
Humans
Lumbar Vertebrae
Male
Medical sciences
Meta-Analysis as Topic
Microsatellite Repeats
Middle Aged
Osteoporosis
Osteoporosis - genetics
Osteoporosis - physiopathology
Osteoporosis. Osteomalacia. Paget disease
Polymorphism
Polymorphism, Genetic
Receptors, Estrogen - genetics
Risk
Risk factors
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Summary:CONTEXT Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor α (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. DESIGN AND SETTING Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers. MAIN OUTCOME MEASURES 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.
ISSN:0098-7484
1538-3598
DOI:10.1001/jama.292.17.2105