A functional SNP regulated by miR-196a-3p in the 3UTR of FGF2 is associated with bone mineral density in the Chinese population
A functional SNP regulated by miR-196a-3p in the 3UTR of FGF2 is associated with bone mineral density in the Chinese population
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FGF2 3UTR 中 miR-196a-3p 调节的功能性 SNP 与中国人群的骨矿物质密度相关
DOI：
10.1002/humu.23216
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发表时间：
2017
期刊：
影响因子：
3.9
通讯作者：
Yang Tie-Lin
中科院分区：
文献类型：
--
作者：
Zhu Dong-Li;Guo Yan;Zhang Y;Dong SS;Xu Wen;Hao Ruo-Han;Chen Xiao-Feng;Yan Han;Yang Shui-Yun;Yang Tie-Lin
先前的研究已确定FGF 2是高加索人骨质疏松症的易感基因。评估不同种族的遗传关联是必要的。此外，阐明易感位点的功能机制对于为治疗研究提供新的靶点具有重要意义。在此，我们对1,300名中国受试者的发现样本进行了FGF 2的10个SNPs基因分型，并检测了其与骨密度（BMD）的相关性。在另一个1,039名中国受试者的样本中重复了名义上显著的结果。我们在FGF 23 ′非翻译区发现一个SNP rs 1048201：C>T与脊柱BMD显著相关（联合队列，P= 1.53×10−3）。表达数量性状位点分析显示rs 1048201也影响FGF 2基因的表达（P= 7.03×10−4）。生物信息学预测表明rs 1048201 T等位基因可破坏miRNA的结合。荧光素酶检测证实C等位基因对FGF 2基因表达有抑制作用。我们发现hsa-miR-196 a-3 p影响FGF 2 mRNA和蛋白水平的表达。总之，我们的研究提供了证据表明功能性SNP rs 1048201与BMD相关，SNP rs 1048201：C>T变体可能通过影响hsa-miR-196 a-3 p的结合而起作用。SNP修饰的miRNA对转录后基因的调控可能是骨质疏松症的潜在发病机制。
Previous studies have identifiedFGF2as a susceptibility gene for osteoporosis in Caucasians. Evaluating the genetic associations in different ethnicities is necessary. Moreover, elucidating the functional mechanism for the susceptibility loci is important to offer new targets for therapeutic studies. Here, we genotyped 10 SNPs inFGF2and tested for associations with bone mineral density (BMD) in a discovery sample of 1,300 Chinese subjects. Nominally significant results were subjected to replication in another sample of 1,039 Chinese subjects. We identified one SNP rs1048201:C>T inFGF23′untranslated region significantly associated with spine BMD (combined cohorts,P= 1.53×10−3). Expression quantitative trait locus analyses revealed that rs1048201 also affectedFGF2gene expression (P= 7.03×10−4). Bioinformatics prediction suggested that rs1048201 T allele could disrupt miRNA binding. Luciferase assay validated that the C allele had a repressive effect onFGF2gene expression. We found that hsa‐miR‐196a‐3p affected expression on both mRNA and protein levels ofFGF2. In conclusion, our study provided evidence that a functional SNP rs1048201 was associated with BMD, and SNP rs1048201:C>T variant may act by affecting binding of hsa‐miR‐196a‐3p. The SNP‐modified posttranscriptional gene regulation by miRNA could be a potentially pathogenetic mechanism of osteoporosis.