TITLE

Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus

AUTHOR(S)
Miller, Clint L.; Anderson, D. Ryan; Kundu, Ramendra K.; Raiesdana, Azad; Nürnberg, Sylvia T.; Diaz, Roxanne; Cheng, Karen; Leeper, Nicholas J.; Chen, Chung-Hsing; Chang, I-Shou; Schadt, Eric E.; Hsiung, Chao Agnes; Assimes, Themistocles L.; Quertermous, Thomas
PUB. DATE
July 2013
SOURCE
PLoS Genetics;Jul2013, Vol. 9 Issue 7, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
ACCESSION #
89657053

 

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