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Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes
John P. A. Ioannidis, MD;
Stuart H. Ralston, MD;
Simon T. Bennett, PhD;
Maria Luisa Brandi, MD, PhD;
Daniel Grinberg, PhD;
Fotini B. Karassa, MD;
Bente Langdahl, MD;
Joyce B. J. van Meurs, PhD;
Leif Mosekilde, MD, DMSci;
Serena Scollen, BSc;
Omar M. E. Albagha, PhD;
Mariona Bustamante, BSc;
Alisoun H. Carey, PhD;
Alison M. Dunning, PhD;
Anna Enjuanes, PhD;
Johannes P. T. M. van Leeuwen, PhD;
Carmelo Mavilia, PhD;
Laura Masi, MD, PhD;
Fiona E. A. McGuigan, PhD;
Xavier Nogues, MD, PhD;
Huibert A. P. Pols, MD, PhD;
David M. Reid, MD;
Stephanie C. E. Schuit, MD, PhD;
Rachael E. Sherlock, BSc;
André G. Uitterlinden, PhD; for the GENOMOS Study
JAMA. 2004;292:2105-2114.
Context Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor  (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.
Author Affiliations: Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (Drs Ioannidis and Karassa); Biomedical Research Institute, Foundation for Research and Technology–Hellas, Ioannina, Greece (Dr Ioannidis); Department of Medicine, Tufts–New England Medical Center, Tufts University School of Medicine, Boston, Mass (Dr Ioannidis); Institute of Medical Sciences, University of Aberdeen Medical School, Aberdeen, Scotland (Drs Ralston, Albagha, Reid, and McGuigan); Oxagen Limited, Abingdon, England (Drs Bennett and Carey and Ms Sherlock); Department of Internal Medicine, University of Florence, Florence, Italy (Drs Brandi, Mavilia, and Masi); Department of Genetics, Faculty of Biology, University of Barcelona, Barcelona, Spain (Dr Grinberg and Ms Bustamante); Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark (Drs Langdahl and Mosekilde); Department of Internal Medicine (Drs van Meurs, van Leeuwen, Pols, Schuit, and Uitterlinden) and Department of Epidemiology and Biostatistics (Drs van Meurs, Pols, Schuit, and Uitterlinden), Erasmus University MC, Rotterdam, the Netherlands; Strangeways Research Laboratory, Cambridge University, Cambridge, England (Ms Scollen and Dr Dunning); and Hospital del Mar–IMIM, UAB, Barcelona, Spain (Drs Enjuanes and Nogues).
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