title: Myocardial Infarction-Associated SNP at 6p24 Interferes With MEF2 Binding and Associates With PHACTR1 Expression Levels in Human Coronary Arteries.
abstract: OBJECTIVE
  Coronary artery disease (CAD), including myocardial infarction (MI), is the main cause of death in the world. Genome-wide association studies have identified dozens of single nucleotide polymorphisms (SNPs) associated with CAD/MI. One of the most robust CAD/MI genetic associations is with intronic SNPs in the gene PHACTR1 on chromosome 6p24. How these PHACTR1 SNPs influence CAD/MI risk, and whether PHACTR1 itself is the causal gene at the locus, is currently unknown.
  
  
  RESULTS
  Using genetic fine-mapping and DNA resequencing experiments, we prioritized an intronic SNP (rs9349379) in PHACTR1 as causal variant. We showed that this variant is an expression quantitative trait locus for PHACTR1 expression in human coronary arteries. Experiments in endothelial cell extracts confirmed that alleles at rs9349379 are differentially bound by the transcription factors myocyte enhancer factor-2. We engineered a deletion of this myocyte enhancer factor-2-binding site using CRISPR/Cas9 genome-editing methodology. Heterozygous endothelial cells carrying this deletion express 35% less PHACTR1. Finally, we found no evidence that PHACTR1 expression levels are induced when stimulating human endothelial cells with vascular endothelial growth factor, tumor necrosis factor-α, or shear stress.
  
  
  CONCLUSIONS
  Our results establish a link between intronic SNPs in PHACTR1, myocyte enhancer factor-2 binding, and transcriptional functions at the locus, PHACTR1 expression levels in coronary arteries and CAD/MI risk. Because PHACTR1 SNPs are not associated with the traditional risk factors for CAD/MI (eg, blood lipids or pressure, diabetes mellitus), our results suggest that PHACTR1 may influence CAD/MI risk through as yet unknown mechanisms in the vascular endothelium.
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec, H1T 1C8, Canada.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Beaudoin
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Rajat M
authors.initials: RM
authors.lastname: Gupta
authors.affiliation: Center of Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec, H1T 1C8, Canada.
authors.forename: Ken Sin
authors.initials: KS
authors.lastname: Lo
authors.affiliation: Center of Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Henderson
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec, H1T 1C8, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Lavoie-St-Amour
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec, H1T 1C8, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Langlois
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rivas
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lehoux
authors.affiliation: Center of Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec, H1T 1C8, Canada.|Department of Medicine, Université de Montréal, 2900 Boul. Édouard-Montpetit, Montréal, Québec, H3T 1J4, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.affiliation: Montreal Heart Institute, 5000 Bélanger Street, Montréal, Québec, H1T 1C8, Canada.|Department of Medicine, Université de Montréal, 2900 Boul. Édouard-Montpetit, Montréal, Québec, H3T 1J4, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
mesh_terms: D000483:Alleles; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D003331:Coronary Vessels / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014472:Umbilicus / Q000098:blood supply; D014680:Veins
chemical_list: D064326:MEF2 Transcription Factors; D008840:Microfilament Proteins; C570134:PHACTR1 protein, human
keywords: coronary artery disease; genetic association studies; myocardial infarction
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