Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes
Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes
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DOI：
10.1001/jama.292.17.2105
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发表时间：
2004-11-03
影响因子：
120.7
通讯作者：
Uitterlinden, AG
中科院分区：
文献类型：
--
作者：
Ioannidis, JPA;Ralston, SH;Uitterlinden, AG
背景骨密度(BMD)和骨折风险都有很强的遗传因素。雌激素受体α(ESR1)基因是骨质疏松症的候选基因，但该领域以往对ESR1基因多态性的研究因样本量小、缺乏标准化和结果不确定而受到阻碍。目的建立3种常见的ESR1基因(内含子1多态Xbal[dbSNP：rs9340799]和Pugl[dbSNP：rs2234693]和启动子TA重复微卫星)及其单倍型是否与BMD和骨折相关的大规模证据。设计和建立个人水平数据的Meta分析，包括标准化基因分型在欧洲8个中心的18 917人。所有骨折和椎体骨折按基因分型。结果在任何遗传对照中，没有观察到中心间的异质性。在校正或非校正分析中，3种多态或单倍型对BMD均无统计学意义的影响，估计遗传对比之间的差异为0.01g/cm(2)或更小。相反，我们发现骨折风险显著降低。在缺乏Xbal识别位点的纯合子女性中，调整后的所有骨折的风险降低了19%(优势比，0.81[95%CI，0.71-0.93]；P=.002)，脊椎骨折的调整优势降低了35%(优势比，0.65[95%CI，0.49-0.87]；P=.003)。对骨折的影响与骨密度无关，在调整后的分析中没有改变。结论ESR1基因是骨折的易感基因，Xbal通过不依赖于骨密度的机制决定骨折风险。我们的研究证明了具有标准化基因分型和临床结果的充足动力研究在确定常见基因变异对复杂疾病的影响方面的价值。
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.