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Hum Mutat. 2009 Aug;30(8):1231-6. doi: 10.1002/humu.21044.

Functional variant in microRNA-196a2 contributes to the susceptibility of congenital heart disease in a Chinese population.

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Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.


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 rs11614913 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 rs11614913 variant affects HOXB8 binding to mature miR-196a. This is the first study to indicate that miR-196a2 rs11614913 plays a role in sporadic CHD susceptibility.

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