Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes

J. P. Ioannidis, S Ralston, S. T. Bennett, M. L. Brandi, D. Grinberg, F. B. Karassa, B. Langdahl, J. B. van Meurs, L. Mosekilde, S. Scollen, Omar M. E. Albagha, M. Bustamante, A. H. Carey, A. M. Dunning, A. Enjuanes, J. P. van Leeuwen, C. Mavilia, L. Masi, Fiona Elizabeth Anne McGuigan, X. NoguesH. A. Pols, David M Reid, S. C. Schuit, R. E. Sherlock, A. G. Uitterlinden, GENOMOS Study

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271 Citations (Scopus)


Context 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 Xbal [dbSNP: rs9340799] and Pvull [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/cm(2) or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an Xbal recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% Cl, 0.71-0.93]; P=.002) and vertebral fractures by 35% (odds ratio, 0.65 [95% Cl, 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 Pvull and TA repeats.
Conclusions ESR1 is a susceptibility gene for fractures, and Xbal 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.

Original languageEnglish
Pages (from-to)2105-2114
Number of pages10
Issue number17
Publication statusPublished - 3 Nov 2004


  • bone-mineral density
  • receptor-alpha gene
  • myocardial-infarction
  • postmenopausal women
  • repeat polymorphism
  • fracture risk
  • meta-analysis
  • association
  • susceptibility
  • haplotype


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