title: Disease-related growth factor and embryonic signaling pathways modulate an enhancer of TCF21 expression at the 6q23.2 coronary heart disease locus.
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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA. clintm@stanford.edu
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.forename: D Ryan
authors.initials: DR
authors.lastname: Anderson
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.forename: Azad
authors.initials: A
authors.lastname: Raiesdana
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Nürnberg
authors.forename: Roxanne
authors.initials: R
authors.lastname: Diaz
authors.forename: Karen
authors.initials: K
authors.lastname: Cheng
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Chen
authors.forename: I-Shou
authors.initials: IS
authors.lastname: Chang
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Chao Agnes
authors.initials: CA
authors.lastname: Hsiung
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D000483:Alleles; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003327:Coronary Disease / Q000235:genetics* / Q000473:pathology; D003331:Coronary Vessels / Q000166:cytology / Q000254:growth & development; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D018808:Transcription Factor AP-1; C491825:TCF21 protein, human