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Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes

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 and Scollen, Serena , et al. (2004) In JAMA - Journal of the American Medical Association 292(17). p.14-2105
Abstract

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 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:... (More)

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 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.

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keywords
Aged, Bone Density, Estrogen Receptor alpha, Female, Femur Neck, Fractures, Bone, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lumbar Vertebrae, Male, Meta-Analysis as Topic, Microsatellite Repeats, Middle Aged, Osteoporosis, Polymorphism, Genetic, Receptors, Estrogen, Risk, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
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JAMA - Journal of the American Medical Association
volume
292
issue
17
pages
10 pages
publisher
American Medical Association
external identifiers
  • scopus:7244234185
  • pmid:15523071
ISSN
0002-9955
DOI
10.1001/jama.292.17.2105
language
English
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bd325f36-109b-40b8-a58b-47d855885ed2
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2018-01-02 11:03:21
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2019-12-10 07:17:24
@article{bd325f36-109b-40b8-a58b-47d855885ed2,
  abstract     = {<p>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.</p><p>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.</p><p>DESIGN AND SETTING: Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers.</p><p>MAIN OUTCOME MEASURES: BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype.</p><p>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.</p><p>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.</p>},
  author       = {Ioannidis, John P A and Ralston, Stuart H and Bennett, Simon T and Brandi, Maria Luisa and Grinberg, Daniel and Karassa, Fotini B and Langdahl, Bente and van Meurs, Joyce B J and Mosekilde, Leif and Scollen, Serena and Albagha, Omar M E and Bustamante, Mariona and Carey, Alisoun H and Dunning, Alison M and Enjuanes, Anna and van Leeuwen, Johannes P T M and Mavilia, Carmelo and Masi, Laura and McGuigan, Fiona E A and Nogues, Xavier and Pols, Huibert A P and Reid, David M and Schuit, Stephanie C E and Sherlock, Rachael E and Uitterlinden, André G},
  issn         = {0002-9955},
  language     = {eng},
  month        = {11},
  number       = {17},
  pages        = {14--2105},
  publisher    = {American Medical Association},
  series       = {JAMA - Journal of the American Medical Association},
  title        = {Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes},
  url          = {http://dx.doi.org/10.1001/jama.292.17.2105},
  doi          = {10.1001/jama.292.17.2105},
  volume       = {292},
  year         = {2004},
}