Common Sequence Variation in FLNB Regulates Bone Structure in Women in the General Population and FLNB mRNA Expression in Osteoblasts In Vitro
Common Sequence Variation in FLNB Regulates Bone Structure in Women in the General Population and FLNB mRNA Expression in Osteoblasts In Vitro
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DOI：
10.1359/jbmr.090530
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发表时间：
2009-12-01
影响因子：
6.2
通讯作者：
Prince, Richard L.
中科院分区：
文献类型：
--
作者：
Wilson, Scott G.;Jones, Michelle R.;Prince, Richard L.
本研究组先前的数据表明BMD与染色体3 p14-p21相关。由于细丝蛋白B（FLNB）基因位于该区域，是骨骼发育不良的原因，并且在我们的生物信息学分析中被鉴定为顶级基因，因此我们假设FLNB在一般人群中调节骨结构中的作用。使用标签单核苷酸多态性（SNP）的方法，一个家庭的研究767名女性同胞，其中3 p14-p21连锁与BMD先前显示。在另外两个数据集中测试了显示BMD相关性的FLNB变体，一项对1085名英国女性双胞胎的研究和一项对1315名澳大利亚女性的人群研究（CAIFOS）。在96个人成骨细胞系中进行基因型表达研究，以在体外检查变体。在基于家族的研究中，rs7637505、rs 9822918、rs 2177153和rs 2001972显示与股骨颈相关（p = 0.0002-0.02）。双胞胎研究进一步支持rs7637505与股骨颈和脊柱BMD之间的相关性（p = 0.02-0.03）。CAIFOS研究进一步表明rs 2177153和rs 9822918与股骨颈BMD之间存在相关性（p = 0.004-0.03）。在rs 2177153的A等位基因携带者中，骨折患病率增加（p = 0.009）。体外研究表明，rs 11130605（本身与rs7637505存在强LD）与FLNB mRNA表达之间存在关联。这些发现表明FLNB的常见变异对女性的骨结构有影响。尽管具有影响的变体的位置不完全一致，但基因5'端的变异可能反映了对FLNB转录效率水平的影响。J Bone Miner Res 2009;24：1989-1997.在线发表于2009年5月18日; doi：10.1359/JBMR.090530
Previous data from our group indicate that BMD is linked to chromosome 3p14-p21. Because the filamin B (FLNB) gene resides in this region, is the cause of skeletal dysplasias, and was identified among the top genes in our bioinformatics analysis, we hypothesized a role for FLNB in the regulation of bone structure in the general population. Using a tag single nucleotide polymorphism (SNP) approach, a family study of 767 female sibs in which the 3p14-p21 linkage with BMD was previously shown was examined. FLNB variants showing a BMD association were tested in two additional data sets, a study of 1085 UK female twins and a population study (CAIFOS) of 1315 Australian women. Genotype-expression studies were performed in 96 human osteoblast lines to examine the variants in vitro. rs7637505, rs9822918, rs2177153, and rs2001972 showed association with femoral neck (p = 0.0002-0.02) in the family-based study. The twin study provided further support for an association between rs7637505 and femoral neck and spine BMD (p = 0.02-0.03). The CAIFOS study further suggested an association between rs2177153 and rs9822918 and femoral neck BMD (p = 0.004-0.03). Prevalent fractures were increased in carriers of the A allele of rs2177153 (p = 0.009). In vitro studies showed association between rs11130605, itself in strong LD with rs7637505, and FLNB mRNA expression. These findings suggest common variants in FLNB have effects on bone structure in women. Although the location of variants having effects is not entirely consistent, variation at the 5' end of the gene may reflect effects on levels of FLNB transcription efficiency. J Bone Miner Res 2009;24:1989-1997. Published online on May 18, 2009; doi: 10.1359/JBMR.090530