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

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

Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative Team

England

2015-12-05T21:05:18Z

2015-05-06

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.

http://www.ncbi.nlm.nih.gov/pubmed/25948407

bmjopen-2014-006920

2044-6055

https://hdl.handle.net/10161/11099

eng

BMJ

BMJ Open

10.1136/bmjopen-2014-006920

GENETICS

SURGERY

Adult

Aged

Biomarkers

Coronary Artery Bypass

Creatine Kinase

Female

Genome-Wide Association Study

Humans

Intraoperative Complications

Male

Middle Aged

Monitoring, Physiologic

Myocardial Infarction

Myocardium

Prognosis

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

Journal article

Li, Yi-Ju|0000-0001-6996-4834

Alexander, John|0000-0002-1444-2462

Mathew, Joseph P|0000-0002-3815-4131

http://www.ncbi.nlm.nih.gov/pubmed/25948407

e006920

5

Anesthesiology

Anesthesiology, Cardiothoracic

Basic Science Departments

Biostatistics & Bioinformatics

Clinical Science Departments

Duke

Duke Clinical Research Institute

Duke Molecular Physiology Institute

Institutes and Centers

Medicine

Medicine, Cardiology

School of Medicine

Surgery

Surgery, Cardiovascular and Thoracic Surgery

Published online

5