ArticlePLoS genetics2014
Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Coronary artery disease-associated variants regulate vascular smooth muscle cell gene expression.Nature cardiovascular research · 2025Article
- Modeling common and rare genetic risk factors of neuropsychiatric disorders in human induced pluripotent stem cells.Schizophrenia research · 2024Review
- Omics Approaches Unveiling the Biology of Human Atherosclerotic Plaques.The American journal of pathology · 2024Review
- Top Five Stories of the Cellular Landscape and Therapies of Atherosclerosis: Current Knowledge and Future Perspectives.Current medical science · 2024Review
- Article
- Of mice and human-specific long noncoding RNAs.Mammalian genome : official journal of the International Mammalian Genome Society · 2022Review
- Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque.Nature cardiovascular research · 2022Article
- Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis.International journal of molecular sciences · 2022Review
- Abnormal expression of long non-coding RNA rhabdomyosarcoma 2-associated transcript (RMST) participates in the pathological mechanism of atherosclerosis by regulating miR-224-3p.Bioengineered · 2022Article
- Association BetweenInternational journal of general medicine · 2022Article
- Differentiated expression of long non-coding RNA-small nucleolar RNA host gene 8 in atherosclerosis and its molecular mechanism.Bioengineered · 2021Article
- Article
- Coronary Artery Disease Genetics Enlightened by Genome-Wide Association Studies.JACC. Basic to translational science · 2021Review
- Fate and State of Vascular Smooth Muscle Cells in Atherosclerosis.Circulation · 2021Review
- HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2.Molecular therapy. Nucleic acids · 2021Article
- Heart Enhancers: Development and Disease Control at a Distance.Frontiers in genetics · 2021Review
- Association of Genetic Variants in miR-217 Gene with Risk of Coronary Artery Disease: A Case-Control Study.Pharmacogenomics and personalized medicine · 2021Article
- Genetic Regulation of Atherosclerosis-Relevant Phenotypes in Human Vascular Smooth Muscle Cells.Circulation research · 2020Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 7 institutions in 3 countries.
Funding
Abstract
Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, resides in the 3' untranslated region (3'-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3' UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with previous studies showing that this variant modulates transcriptional regulation through activator protein 1 (AP-1), suggests a unique bimodal level of complexity previously unreported for disease-associated variants.
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