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 Vol. 292; no. 17; pp. 2105 - 2114 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chicago, IL
American Medical Association
03.11.2004
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0098-7484 1538-3598 |
DOI: | 10.1001/jama.292.17.2105 |