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.
Highlights
Coronary heart disease (CHD), involving atherosclerosis and myocardial infarction (MI), is a genetically complex trait and represents the leading cause of mortality worldwide
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
SNPs by examining the allele specific expression (ASE) in heterozygous individuals for the transcript variant rs12190287, which is located in the 39 untranslated region (39-UTR) of the TCF21 gene
Summary
Coronary heart disease (CHD), involving atherosclerosis and myocardial infarction (MI), is a genetically complex trait and represents the leading cause of mortality worldwide. Meta-analyses of genome-wide association studies (GWAS) for CHD have identified 46 replicated loci in subjects of European descent [1]. Of these loci, the region at 6q23.2 contains the lead variant, rs12190287, which had the lowest P value among several SNPs that reached the genome-wide significance threshold in this locus [2]. The association of TCF21 with CHD is compelling, given its association with fundamental cardiovascular embryonic The TCF21 locus association with CHD was recently confirmed in a meta-analysis of predominantly European subjects genotyped with the Cardio-Metabochip (Illumina) and in a three stage GWAS for CHD in individuals of Han Chinese descent [1,3].
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