Proposed model of signaling pathways converging on miR-224-<i>TCF21</i> interaction at rs12190287.

<p>Previous studies elucidated a <i>cis</i>-regulatory mechanism by which the lead SNP associated with CHD at 6q23.2, rs12190287, was shown to disrupt trans-activating AP-1 binding by the minor protective allele (G). This resulted in altered growth factor mediated transcriptional activation, chromatin organization and allele-specific <i>TCF21</i> gene expression in human coronary artery smooth muscle cells (HCASMC). The <i>trans</i>-repressing factor, Wilms tumor 1 (WT1) was also shown to counter-regulate the positive effects of AP-1 at rs12190287 and preferentially associate with the major risk allele (C). Herein we describe a post-transcriptional <i>cis</i>-regulatory mechanism by which the minor protective allele alters a perfect seed match of miR-224 in the 3′-UTR of <i>TCF21</i>. Altered RNA structure is predicted to account for differential miRNA binding kinetics, and regulation of transcription. Further, both PDGF-BB and TGF-β upstream stimuli in HCASMC may account for the miR-224 mediated allele-specific expression at rs12190287. Additionally, both NFκB and Wnt upstream signals have been proposed to regulate miR-224 in tumor cells, and may potentially participate in the described mechanisms in HCASMC. Taken, together dysregulation of <i>TCF21</i> is predicted to account for altered smooth muscle cell (SMC) response to injury due to phenotypic modulation from a differentiated to proliferating SMC, leading to increased risk for CHD.