Functional Variant in microRNA-196a2 Contributes to the Susceptibility of Congenital Heart Disease in a Chinese Population
Functional Variant in microRNA-196a2 Contributes to the Susceptibility of Congenital Heart Disease in a Chinese Population
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microRNA-196a2的功能变异导致中国人群患先天性心脏病的风险增加
DOI：
10.1002/humu.21044
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发表时间：
2009-08-01
期刊：
影响因子：
3.9
通讯作者：
Chen, Yijiang
中科院分区：
文献类型：
--
作者：
Xu, Jing;Hu, Zhibin;Chen, Yijiang
Hox基因簇在不同物种的心脏间隔到瓣膜形成过程中发挥重要作用，miR-196a-HOXB8-Sonic hedgehog信号通路特别受关注。最近，我们发现miR-196a2序列中rs11614913的遗传变异可以改变成熟miR-196a的表达和靶mRNA的结合；这一观察结果使我们假设rs11614913可能影响散发性先天性心脏病（CHD）的易感性。我们在中国开展了一项三阶段的冠心病病例对照研究，通过对1324例冠心病患者和1783例非冠心病对照者进行miR-196a2 rs11614913和其他三个pre-miRNA snp （miR-146a rs2910164、miR-149 rs2292832和miR-499 rs3746444）的基因分型来检验我们的假设。我们发现，rs 11614913 CC与所有三个阶段冠心病风险的显著增加相关（P = 6.81 × 10(-6)）。在29例冠心病心脏组织样本的基因型-表型相关分析中，rs11614913 CC与成熟miR-196a表达显著升高相关（P=0.001）。体外结合实验进一步揭示rs 11614913变异影响HOXB8与成熟miR-196a的结合。这是首次研究表明miR-196a2 rs 11614913在散发性冠心病易感性中起作用。[j] .中国生物医学工程学报，2009,31(2):481 - 481。(C) 2009 Wiley-Liss, Inc。
Hox gene clusters play an important role during cardiac septation to valve formation in different species, and the miR-196a-HOXB8-Sonic hedgehog signaling pathway is of particular interest. Recently, we found that a genetic variant of rs11614913 in the miR-196a2 sequence could alter mature miR-196a expression and target mRNA binding; this observation led us to hypothesize that rs11614913 might influence susceptibility to sporadic congenital heart disease (CHD). We conducted a three-stage case-control study of CHD in Chinese to test our hypothesis by genotyping miR-196a2 rs11614913 and three other pre-miRNA SNPs (miR-146a rs2910164, miR-149 rs2292832, and miR-499 rs3746444) in 1,324 CHD cases and 1,783 non,CHD controls. We found that rs 11614913 CC was associated with a significantly increased risk of CHD in all three stages combined (P = 6.81 x 10(-6)). In a genotype-phenotype correlation analysis using 29 cardiac tissue samples of CHD, rs11614913 CC was associated with significantly increased mature miR-196a expression (P=0.001). In vitro binding assays further revealed that the rs 11614913 variant affects HOXB8 binding to mature miR-196a. This is the first study to indicate that miR-196a2 rs 11614913 plays a role in sporadic CHD susceptibility. Hum Mutat 30,1231-1236, 2009. (C) 2009 Wiley-Liss, Inc.