The-9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPα and FOXA1 binding is associated with osteoporosis
The-9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPα and FOXA1 binding is associated with osteoporosis
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DOI：
10.1016/j.bone.2009.03.676
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发表时间：
2009-08-01
期刊：
影响因子：
4.1
通讯作者：
Kung, Annie W. C.
中科院分区：
文献类型：
--
作者：
Huang, Qing-Yang;Li, Gloria H. Y.;Kung, Annie W. C.
越来越多的证据表明，导致单基因疾病的基因也会导致普通人群中类似的复杂疾病。我们试图确定7个单基因骨病基因（CLCN 7、TCIRGI、SOST、CA 2、CSTK、TGFB 1和SLC 26 A2）的等位基因变异是否与中国正常人群的骨质疏松/骨密度（BMD）变异有关。我们在1243名中国低BMD受试者中进行了一项基于全基因标签SNP的关联研究（Z评分= + 1.0）。选择22个标签SNP，并使用高通量Sequenom基因分型平台进行基因分型。通过Haploview和二元逻辑回归分析进行等位基因和单倍型关联检验。sclerostin基因上游调控区-9247多态性rs 1230399与脊柱、股骨颈、转子和全髋BMD有显著的基因型/等位基因相关性（P = 0.03-0.004）。rs 1230399的T等位基因增加了骨质疏松的风险（OR = 1.52，P = 0.005）。计算分析表明，rs 1230399位于调节雌激素受体功能的两个协同转录因子C/EBP α和FOXA 1的核心共有识别位点。T -> C多态性消除了C/EBP α和FOXA 1与硬化蛋白基因的结合。我们的数据表明rs 1230399和BMD之间通过雌激素ER α/FOXA 1信号通路的长距离增强子驱动的机制联系。(C)2009 Elsevier Inc. All rights reserved.
Accumulating evidence shows that genes that Cause monogenic diseases also contribute to similar complex disease in the general population. We sought to determine whether the allelic variation in seven monogenic bone disease genes (CLCN7, TCIRGI, SOST, CA2, CSTK, TGFB1 and SLC26A2) contributes to osteoporosis/bone mineral density (BMD) variation in the normal Chinese population. We conducted a gene-wide tag SNP-based association study in 1243 Chinese Subjects with low BMD (Z-scores = + 1.0). Twenty-two tag SNPs were selected and genotyped by using the high-through put Sequenom genotyping platform. Allelic and haplotype association tests were conducted by Haploview and binary logistic regression analyses. The -9247 polymorphism rs 1230399 in the upstream regulatory region of the sclerostin gene showed significant genotypic/allelic associations with spine, femoral neck, trochanter and total hip BMD (P = 0.03-0.004). The T-allele of rs1230399 increased the risk of osteoporosis (OR = 1.52, P = 0.005). Computational analysis showed that rs1230399 is located at the core consensus recognition site of two cooperating transcription factors C/EBP alpha and FOXA1 that modulate estrogen receptor function. T -> C polymorphism abolishes the binding of both C/EBP alpha and FOXA1 to the sclerostin gene. Our data suggest a mechanistic link between rs1230399 and BMD through estrogen ER alpha/FOXA1 signaling pathways driven by long-distance enhancers. (C) 2009 Elsevier Inc. All rights reserved.