title: Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery.
abstract: OBJECTIVE
  Identification of patient subpopulations susceptible to develop myocardial infarction (MI) or, conversely, those displaying either intrinsic cardioprotective phenotypes or highly responsive to protective interventions remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with perioperative MI in patients undergoing coronary artery bypass grafting using genome-wide association methodology.
  
  
  METHODS
  107 secondary and tertiary cardiac surgery centres across the USA.
  
  
  METHODS
  We conducted a stage I genome-wide association study (GWAS) in 1433 ethnically diverse patients of both genders (112 cases/1321 controls) from the Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMAGIC) study, and a stage II analysis in an expanded population of 2055 patients (225 cases/1830 controls) combined from the GeneMAGIC and Duke Perioperative Genetics and Safety Outcomes (PEGASUS) studies. Patients undergoing primary non-emergent coronary bypass grafting were included.
  
  
  METHODS
  The primary outcome variable was perioperative MI, defined as creatine kinase MB isoenzyme (CK-MB) values ≥10× upper limit of normal during the first postoperative day, and not attributable to preoperative MI. Secondary outcomes included postoperative CK-MB as a quantitative trait, or a dichotomised phenotype based on extreme quartiles of the CK-MB distribution.
  
  
  RESULTS
  Following quality control and adjustment for clinical covariates, we identified 521 single nucleotide polymorphisms in the stage I GWAS analysis. Among these, 8 common variants in 3 genes or intergenic regions met p<10(-5) in stage II. A secondary analysis using CK-MB as a quantitative trait (minimum p=1.26×10(-3) for rs609418), or a dichotomised phenotype based on extreme CK-MB values (minimum p=7.72×10(-6) for rs4834703) supported these findings. Pathway analysis revealed that genes harbouring top-scoring variants cluster in pathways of biological relevance to extracellular matrix remodelling, endoplasmic reticulum-to-Golgi transport and inflammation.
  
  
  CONCLUSIONS
  Using a two-stage GWAS and pathway analysis, we identified and prioritised several potential susceptibility loci for perioperative MI.
authors.affiliation: Division of Cardiothoracic Anesthesiology, Duke University, Durham, North Carolina, USA.
authors.forename: Miklos D
authors.initials: MD
authors.lastname: Kertai
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA Duke Molecular Physiology Institute; Duke University, Durham, North Carolina, USA.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA.
authors.forename: Yen-Wei
authors.initials: YW
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA.
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Division of Cardiology, Duke University, Durham, North Carolina, USA Duke Clinical Research Institute; Duke University, Durham, North Carolina, USA.
authors.forename: John
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Division of Cardiothoracic Anesthesiology, Duke University, Durham, North Carolina, USA Duke Clinical Research Institute; Duke University, Durham, North Carolina, USA.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Newman
authors.affiliation: Cardiac Surgery; Duke University, Durham, North Carolina, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Smith
authors.affiliation: Duke Clinical Research Institute; Duke University, Durham, North Carolina, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph
authors.affiliation: Division of Cardiothoracic Anesthesiology, Duke University, Durham, North Carolina, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mathew
authors.affiliation: Division of Cardiothoracic Anesthesiology, Duke University, Durham, North Carolina, USA Duke Clinical Research Institute; Duke University, Durham, North Carolina, USA.
authors.forename: Mihai V
authors.identifier: http://orcid.org/0000-0001-5539-4674
authors.initials: MV
authors.lastname: Podgoreanu
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001026:Coronary Artery Bypass / Q000009:adverse effects* / Q000379:methods; D003402:Creatine Kinase / Q000378:metabolism*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007431:Intraoperative Complications / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D009203:Myocardial Infarction / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011379:Prognosis
chemical_list: D015415:Biomarkers; D003402:Creatine Kinase
keywords: GENETICS; SURGERY