Zhu Dong-Li, Guo Yan, Zhang Yan, Dong Shan-Shan, Xu Wen, Hao Ruo-Han, Chen Xiao-Feng, Yan Han, Yang Shui-Yun, Yang Tie-Lin
Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Center for Translational Medicine, Xi'an Jiaotong University College of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Hum Mutat. 2017 Jun;38(6):725-735. doi: 10.1002/humu.23216. Epub 2017 Apr 13.
Previous studies have identified FGF2 as 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 in FGF2 and 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 in FGF2 3'untranslated region significantly associated with spine BMD (combined cohorts, P = 1.53×10 ). Expression quantitative trait locus analyses revealed that rs1048201 also affected FGF2 gene expression (P = 7.03×10 ). Bioinformatics prediction suggested that rs1048201 T allele could disrupt miRNA binding. Luciferase assay validated that the C allele had a repressive effect on FGF2 gene expression. We found that hsa-miR-196a-3p affected expression on both mRNA and protein levels of FGF2. 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.
以往研究已将FGF2确定为高加索人群骨质疏松症的一个易感基因。评估不同种族中的遗传关联很有必要。此外，阐明易感位点的功能机制对于为治疗研究提供新靶点很重要。在此，我们对FGF2中的10个单核苷酸多态性（SNP）进行基因分型，并在1300名中国受试者的发现样本中测试其与骨密度（BMD）的关联。名义上具有显著意义的结果在另外1039名中国受试者的样本中进行重复验证。我们在FGF2 3'非翻译区鉴定出一个SNP rs1048201:C>T与脊柱骨密度显著相关（合并队列，P = 1.53×10 ）。表达数量性状位点分析显示rs1048201也影响FGF2基因表达（P = 7.03×10 ）。生物信息学预测表明rs1048201的T等位基因可能破坏微小RNA（miRNA）结合。荧光素酶测定验证了C等位基因对FGF2基因表达具有抑制作用。我们发现hsa-miR-196a-3p在mRNA和蛋白质水平上均影响FGF2的表达。总之，我们的研究提供了证据表明功能性SNP rs1048201与骨密度相关，且SNP rs1048201:C>T变异可能通过影响hsa-miR-196a-3p的结合起作用。miRNA对SNP修饰的转录后基因调控可能是骨质疏松症的一种潜在致病机制。
