Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery

• Published in: BMJ open Vol. 5; no. 5; p. e006920
• Main Authors: Kertai, Miklos D, Li, Yi-Ju, Li, Yen-Wei, Ji, Yunqi, Alexander, John, Newman, Mark F, Smith, Peter K, Joseph, Diane, Mathew, Joseph P, Podgoreanu, Mihai V
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 06.05.2015; BMJ Publishing Group
• Subjects: Adult; Aged; Biomarkers - metabolism; Coronary Artery Bypass - adverse effects; Coronary Artery Bypass - methods; Coronary vessels; Creatine Kinase - metabolism; Datasets; Female; Genes; Genetics; Genetics and Genomics; Genome-Wide Association Study; Genomes; Heart surgery; Humans; Integrated approach; Intraoperative Complications - diagnosis; Male; Methods; Middle Aged; Monitoring, Physiologic; Mortality; Myocardial Infarction - diagnosis; Myocardial Infarction - etiology; Myocardial Infarction - metabolism; Myocardium - metabolism; Prognosis; Quality control; Studies; SURGERY; GENETICS
• ISSN: 2044-6055; 2044-6055
• DOI: 10.1136/bmjopen-2014-006920

Objectives 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. Setting 107 secondary and tertiary cardiac surgery centres across the USA. Participants 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. Primary and secondary outcome measures 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.