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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 |
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| container_title | JAMA : the journal of the American Medical Association |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1001/jama.292.17.2105 |
| format | article |
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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.</description><identifier>ISSN: 0098-7484</identifier><identifier>EISSN: 1538-3598</identifier><identifier>DOI: 10.1001/jama.292.17.2105</identifier><identifier>PMID: 15523071</identifier><identifier>CODEN: JAMAAP</identifier><language>eng</language><publisher>Chicago, IL: American Medical Association</publisher><subject>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</subject><ispartof>JAMA : the journal of the American Medical Association, 2004-11, Vol.292 (17), p.2105-2114</ispartof><rights>2004 INIST-CNRS</rights><rights>Copyright American Medical Association Nov 3, 2004</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a426t-72009bb24574afa9c98c045955acef12a5dff00b0077b99b8e27aafa8b8625d23</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16227921$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15523071$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ioannidis, John P. A</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><creatorcontrib>Bennett, Simon T</creatorcontrib><creatorcontrib>Brandi, Maria Luisa</creatorcontrib><creatorcontrib>Grinberg, Daniel</creatorcontrib><creatorcontrib>Karassa, Fotini B</creatorcontrib><creatorcontrib>Langdahl, Bente</creatorcontrib><creatorcontrib>van Meurs, Joyce B. J</creatorcontrib><creatorcontrib>Mosekilde, Leif</creatorcontrib><creatorcontrib>Scollen, Serena</creatorcontrib><creatorcontrib>Albagha, Omar M. E</creatorcontrib><creatorcontrib>Bustamante, Mariona</creatorcontrib><creatorcontrib>Carey, Alisoun H</creatorcontrib><creatorcontrib>Dunning, Alison M</creatorcontrib><creatorcontrib>Enjuanes, Anna</creatorcontrib><creatorcontrib>van Leeuwen, Johannes P. T. M</creatorcontrib><creatorcontrib>Mavilia, Carmelo</creatorcontrib><creatorcontrib>Masi, Laura</creatorcontrib><creatorcontrib>McGuigan, Fiona E. A</creatorcontrib><creatorcontrib>Nogues, Xavier</creatorcontrib><creatorcontrib>Pols, Huibert A. P</creatorcontrib><creatorcontrib>Reid, David M</creatorcontrib><creatorcontrib>Schuit, Stephanie C. E</creatorcontrib><creatorcontrib>Sherlock, Rachael E</creatorcontrib><creatorcontrib>Uitterlinden, André G</creatorcontrib><creatorcontrib>GENOMOS Study, for the</creatorcontrib><creatorcontrib>GENOMOS Study</creatorcontrib><title>Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes</title><title>JAMA : the journal of the American Medical Association</title><addtitle>JAMA</addtitle><description>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.</description><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>Bone Density - genetics</subject><subject>Bones</subject><subject>Diseases of the osteoarticular system</subject><subject>Estrogen Receptor alpha</subject><subject>Female</subject><subject>Femur Neck</subject><subject>Fractures</subject><subject>Fractures, Bone - epidemiology</subject><subject>Fractures, Bone - genetics</subject><subject>General aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genotype</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Lumbar Vertebrae</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Meta-Analysis as Topic</subject><subject>Microsatellite Repeats</subject><subject>Middle Aged</subject><subject>Osteoporosis</subject><subject>Osteoporosis - genetics</subject><subject>Osteoporosis - physiopathology</subject><subject>Osteoporosis. Osteomalacia. Paget disease</subject><subject>Polymorphism</subject><subject>Polymorphism, Genetic</subject><subject>Receptors, Estrogen - genetics</subject><subject>Risk</subject><subject>Risk factors</subject><issn>0098-7484</issn><issn>1538-3598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqF0c9LwzAUB_AgipvTu16kCHprzY-mSY4y5xQGG_44lzRLMKNtZtIe9t-bucnAi7k8eO_DI_kGgEsEMwQhul_JRmZY4AyxDCNIj8AQUcJTQgU_BkMIBU9ZzvMBOAthBeNBhJ2CAaIUE8jQECwerTHa67azsk6mutWdVckk9lQXEmeSydsr-uknC1dvGufXnzY0cdQm89Bpt3beBRuSed8p1-hwDk6MrIO-2NcR-HiavI-f09l8-jJ-mKUyx0WXMhwvV1U4pyyXRgoluII5FZRKpQ3Cki6NgbCCkLFKiIprzGSEvOIFpktMRuBut3ft3VevQ1c2Nihd17LVrg9lwSDhBaX_QsQYinnBCG_-wJXrfRsfUWKESJEXaIuu96ivGr0s19420m_K30QjuN0DGZSsjZetsuHgCoyZwFt3tXPxCw9TIWIw5BsgsYw7</recordid><startdate>20041103</startdate><enddate>20041103</enddate><creator>Ioannidis, John P. A</creator><creator>Ralston, Stuart H</creator><creator>Bennett, Simon T</creator><creator>Brandi, Maria Luisa</creator><creator>Grinberg, Daniel</creator><creator>Karassa, Fotini B</creator><creator>Langdahl, Bente</creator><creator>van Meurs, Joyce B. J</creator><creator>Mosekilde, Leif</creator><creator>Scollen, Serena</creator><creator>Albagha, Omar M. E</creator><creator>Bustamante, Mariona</creator><creator>Carey, Alisoun H</creator><creator>Dunning, Alison M</creator><creator>Enjuanes, Anna</creator><creator>van Leeuwen, Johannes P. T. M</creator><creator>Mavilia, Carmelo</creator><creator>Masi, Laura</creator><creator>McGuigan, Fiona E. A</creator><creator>Nogues, Xavier</creator><creator>Pols, Huibert A. P</creator><creator>Reid, David M</creator><creator>Schuit, Stephanie C. E</creator><creator>Sherlock, Rachael E</creator><creator>Uitterlinden, André G</creator><creator>GENOMOS Study, for the</creator><general>American Medical Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TS</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20041103</creationdate><title>Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes</title><author>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. 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Osteomalacia. Paget disease</topic><topic>Polymorphism</topic><topic>Polymorphism, Genetic</topic><topic>Receptors, Estrogen - genetics</topic><topic>Risk</topic><topic>Risk factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ioannidis, John P. A</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><creatorcontrib>Bennett, Simon T</creatorcontrib><creatorcontrib>Brandi, Maria Luisa</creatorcontrib><creatorcontrib>Grinberg, Daniel</creatorcontrib><creatorcontrib>Karassa, Fotini B</creatorcontrib><creatorcontrib>Langdahl, Bente</creatorcontrib><creatorcontrib>van Meurs, Joyce B. J</creatorcontrib><creatorcontrib>Mosekilde, Leif</creatorcontrib><creatorcontrib>Scollen, Serena</creatorcontrib><creatorcontrib>Albagha, Omar M. 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A</au><au>Ralston, Stuart H</au><au>Bennett, Simon T</au><au>Brandi, Maria Luisa</au><au>Grinberg, Daniel</au><au>Karassa, Fotini B</au><au>Langdahl, Bente</au><au>van Meurs, Joyce B. J</au><au>Mosekilde, Leif</au><au>Scollen, Serena</au><au>Albagha, Omar M. E</au><au>Bustamante, Mariona</au><au>Carey, Alisoun H</au><au>Dunning, Alison M</au><au>Enjuanes, Anna</au><au>van Leeuwen, Johannes P. T. M</au><au>Mavilia, Carmelo</au><au>Masi, Laura</au><au>McGuigan, Fiona E. A</au><au>Nogues, Xavier</au><au>Pols, Huibert A. P</au><au>Reid, David M</au><au>Schuit, Stephanie C. E</au><au>Sherlock, Rachael E</au><au>Uitterlinden, André G</au><au>GENOMOS Study, for the</au><aucorp>GENOMOS Study</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes</atitle><jtitle>JAMA : the journal of the American Medical Association</jtitle><addtitle>JAMA</addtitle><date>2004-11-03</date><risdate>2004</risdate><volume>292</volume><issue>17</issue><spage>2105</spage><epage>2114</epage><pages>2105-2114</pages><issn>0098-7484</issn><eissn>1538-3598</eissn><coden>JAMAAP</coden><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><abstract>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.</abstract><cop>Chicago, IL</cop><pub>American Medical Association</pub><pmid>15523071</pmid><doi>10.1001/jama.292.17.2105</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0098-7484 |
| ispartof | JAMA : the journal of the American Medical Association, 2004-11, Vol.292 (17), p.2105-2114 |
| issn | 0098-7484 1538-3598 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67038655 |
| source | American Medical Association Current Titles |
| 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 |
| title | Differential Genetic Effects of ESR1 Gene Polymorphisms on Osteoporosis Outcomes |
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