Disease-related growth factor and embryonic signaling pathways modulate an enhancer of TCF21 expression at the 6q23.2 coronary heart disease locus

• Published in: PLoS genetics Vol. 9; no. 7; p. e1003652
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-07-2013; Public Library of Science (PLoS)
• Subjects: Alleles; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biology; Cardiovascular disease; Cell Differentiation - genetics; Cells, Cultured; Coronary Disease - genetics; Coronary Disease - pathology; Coronary heart disease; Coronary vessels; Coronary Vessels - cytology; Coronary Vessels - growth & development; Embryonic development; Enhancer Elements, Genetic; Experiments; Gene expression; Gene Expression Regulation, Developmental; Genetic aspects; Genome-Wide Association Study; Genomes; Growth factors; Haplotypes; Health aspects; Heart; Humans; Medical research; Medicine; Meta-analysis; Myocytes, Smooth Muscle - cytology; Physiological aspects; Polymorphism, Single Nucleotide; Proteins; Receptor, Platelet-Derived Growth Factor beta - genetics; Receptor, Platelet-Derived Growth Factor beta - metabolism; Rodents; Signal Transduction; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Wilms Tumor - genetics; Wilms Tumor - metabolism; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003652

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.