Coronary Heart Disease-Associated Variation in Disrupts a miR-224 Binding Site and miRNA-Mediated Regulation

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Both genetic and environmental factors cumulatively contribute to coronary heart disease risk in human populations. Large-scale meta-analyses of genome-wide association studies have now leveraged common genetic variation to identify multiple sites of disease susceptibility; however, the causal mechanisms for these associations largely remain elusive. One of these disease-associated variants, rs12190287, resides in the 3′untranslated region of the vascular developmental transcription factor, TCF21. Intriguingly, this variant is shown to disrupt the seed binding sequence for microRNA-224, and through altered RNA secondary structure and binding kinetics, leads to dysregulated TCF21 gene expression in response to disease-relevant stimuli. Importantly TCF21 and miR-224 expression levels were perturbed in human atherosclerotic lesions. Along with our previous reports on the transcriptional regulatory mechanisms altered by this variant, these studies shed new light on the complex heritable mechanisms of coronary heart disease risk that are amenable to therapeutic intervention.

Vyšlo v časopise: Coronary Heart Disease-Associated Variation in Disrupts a miR-224 Binding Site and miRNA-Mediated Regulation. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004263
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004263

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