miR-138 modulates cardiac morphogenesis in zebrafish. We explored whether a genetic polymorphism in miR-138 might contribute to the occurrence of sporadic congenital heart disease (CHD) and the potential mechanism. We performed a case-control study consisting of 857 CHD cases and 938 non-CHD controls by genotyping miR-138 in a Chinese population. Two SNPs, including rare rs139365823 located in the pre-miR-138 sequence and rs76987351 located in the pri-miR-138 sequence, were identified by sequencing miR-138. The results demonstrated that the genotypes and allele frequencies of the rs139365823 minor allele A were significantly associated with the increased risk of CHD cases overall or in the Tetralogy of Fallot (TOF) subtype, but not with the rs76987351 A/G allele. Real-time PCR data showed that the rs139365823 minor allele A significantly increased the expression of mature miR-138, whereas the rs76987351 minor allele A had the opposite effect. As TOF is caused by severe outflow tract (OFT) development and an alignment defect, we identified Dvl2, involved in OFT development, as a direct target of miR-138. Further, the rs139365823 minor allele A enhanced the miR-138-mediated inhibitory regulation of Dvl2. Taken together, our results demonstrated for the first time that the functional variant rs139365823 in pre-miR-138 altered the expression of mature miR-138 and its inhibitory effect on target genes and conferred the risk for CHD in the population studied here.
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