Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes

John P A Ioannidis, Stuart H. Ralston, Simon T. Bennett, Maria Luisa Brandi, Daniel Grinberg, Fotini B. Karassa, Bente Langdahl, Joyce B J Van Meurs, Leif Mosekilde, Serena Scollen, Omar Al Bagha, Mariona Bustamante, Alisoun H. Carey, Alison M. Dunning, Anna Enjuanes, Johannes P T M Van Leeuwen, Carmelo Mavilia, Laura Masi, Fiona E A McGuigan, Xavier NoguesHuibert A P Pols, David M. Reid, Stephanie C E Schuit, Rachael E. Sherlock, André G. Uitterlinden

Research output: Contribution to journalArticle

249 Citations (Scopus)

Abstract

Context: Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor aα (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/cm2 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% 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 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
JournalJournal of the American Medical Association
Volume292
Issue number17
DOIs
Publication statusPublished - 3 Nov 2004
Externally publishedYes

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Bone Density
Osteoporosis
Genes
Bone Fractures
Haplotypes
Odds Ratio
Fracture Fixation
Femur Neck
Estrogen Receptors
Microsatellite Repeats
Sample Size
Introns
Meta-Analysis
Spine
Genotype
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ioannidis, J. P. A., Ralston, S. H., Bennett, S. T., Brandi, M. L., Grinberg, D., Karassa, F. B., ... Uitterlinden, A. G. (2004). Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. Journal of the American Medical Association, 292(17), 2105-2114. https://doi.org/10.1001/jama.292.17.2105

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; Scollen, Serena; Al Bagha, Omar; 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.

In: Journal of the American Medical Association, Vol. 292, No. 17, 03.11.2004, p. 2105-2114.

Research output: Contribution to journalArticle

Ioannidis, JPA, Ralston, SH, Bennett, ST, Brandi, ML, Grinberg, D, Karassa, FB, Langdahl, B, Van Meurs, JBJ, Mosekilde, L, Scollen, S, Al Bagha, O, Bustamante, M, Carey, AH, Dunning, AM, Enjuanes, A, Van Leeuwen, JPTM, Mavilia, C, Masi, L, McGuigan, FEA, Nogues, X, Pols, HAP, Reid, DM, Schuit, SCE, Sherlock, RE & Uitterlinden, AG 2004, 'Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes', Journal of the American Medical Association, vol. 292, no. 17, pp. 2105-2114. https://doi.org/10.1001/jama.292.17.2105
Ioannidis JPA, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB et al. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. Journal of the American Medical Association. 2004 Nov 3;292(17):2105-2114. https://doi.org/10.1001/jama.292.17.2105
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 ; Al Bagha, Omar ; 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. / Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. In: Journal of the American Medical Association. 2004 ; Vol. 292, No. 17. pp. 2105-2114.
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abstract = "Context: Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor aα (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/cm2 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{\%} 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 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.",
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AU - Ioannidis, John P A

AU - Ralston, Stuart H.

AU - Bennett, Simon T.

AU - Brandi, Maria Luisa

AU - Grinberg, Daniel

AU - Karassa, Fotini B.

AU - Langdahl, Bente

AU - Van Meurs, Joyce B J

AU - Mosekilde, Leif

AU - Scollen, Serena

AU - Al Bagha, Omar

AU - Bustamante, Mariona

AU - Carey, Alisoun H.

AU - Dunning, Alison M.

AU - Enjuanes, Anna

AU - Van Leeuwen, Johannes P T M

AU - Mavilia, Carmelo

AU - Masi, Laura

AU - McGuigan, Fiona E A

AU - Nogues, Xavier

AU - Pols, Huibert A P

AU - Reid, David M.

AU - Schuit, Stephanie C E

AU - Sherlock, Rachael E.

AU - Uitterlinden, André G.

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