Functional Variant in microRNA-196a2 Contributes to the Susceptibility of Congenital Heart Disease in a Chinese Population

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.