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

Abstract

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1136/bmjopen-2014-006920

Publication Info

Kertai, Miklos D, Yi-Ju Li, Yen-Wei Li, Yunqi Ji, John Alexander, Mark F Newman, Peter K Smith, Diane Joseph, et al. (2015). Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery. BMJ Open, 5(5). p. e006920. 10.1136/bmjopen-2014-006920 Retrieved from https://hdl.handle.net/10161/11099.

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Scholars@Duke

Li

Yi-Ju Li

Professor of Biostatistics & Bioinformatics

My research interest is in statistical genetics, including statistical method development and its application for understanding the genetic predisposition of human complex diseases. Here is the list of research topics:

  • Statistical genetics: development of family-based association methods for quantitative traits with or without censoring and for detecting X-linked genes for disease risk.  With the availability of next generation sequencing data, we have ongoing projects to develop the association methods for testing rare variants for different phenotypic measures.  
  • Genetics of Alzheimer's disease (AD) and Fuchs endothelial corneal dystrophy (FECD).
  • Genetic basis of age-at-onset of Alzheimer disease. 
  • Peri-operative genomic studies. Investigate the genetic risk factors for postoperative outcomes of patients underwent non-emergent coronary artery bypass grafting with cardiopulmonary bypass.
Alexander

John Hunter Peel Alexander

Professor of Medicine

John H. Alexander, MD, MHS is a cardiologist and Professor of Medicine in the Department of Medicine, Division of Cardiology at Duke University School of Medicine, as well as the Vice Chief, Clinical Research in the Division of Cardiology. He is the Director of Cardiovascular Research at the Duke Clinical Research Institute where he oversees a large group of clinical research faculty and a broad portfolio of cardiovascular clinical trials and observational clinical research programs. He is a member of the American Society of Clinical Investigation.

Dr. Alexander’s clinical interests are in acute and general cardiovascular disease, valvular heart disease, and echocardiology. His research is focused on the translation of novel therapeutic concepts into clinical data through clinical trials, specifically on the therapeutics of acute coronary syndromes, chronic coronary artery disease, and cardiac surgery and on novel methodological approaches to clinical trials. He was on the Executive Committee of the ARISTOTLE trial of apixaban in patients with atrial fibrillation and was the Principal Investigator of the APPRAISE-2 trial of apixaban in patients with acute coronary syndromes.

Dr. Alexander has published extensively and has served as the principal investigator of numerous multicenter clinical trials. He currently serves as the co-chair of the Clinical Trial Transformation Initiative (CTTI).

Newman

Mark Franklin Newman

Merel H. Harmel Distinguished Professor Emeritus of Anesthesiology

Best known for his work in assessing and improving clinical outcomes and quality of life following cardiac surgery, Dr. Mark Newman is President of the Duke Private Diagnostic Clinic (The Duke Faculty Practice Organization) and the Merel H. Harmel Professor of Anesthesiology at Duke University Medical Center. In addition, Dr. Newman developed the Multicenter Perioperative Outcomes Research Group of the Duke Clinical Research Institute established at Duke in 2001 to further the study of strategies to improve the outcomes of patients undergoing surgery and anesthesia. Dr. Newman has received funding from the National Institute on Aging, the American Heart Association, the National Heart, Lung and Blood Institute, the Anesthesia Patient Safety Foundation, and the International Anesthesia Research Society  to investigate the impact of perioperative outcomes (neurocognitive decline, stroke, myocardial infarction, renal injury) on quantity and quality of life following cardiac surgery and resulting in numerous seminal publications in the New England Journal of Medicine, JAMA and Lancet. Dr. Newman is a popular lecturer and speaker, having appeared on NBC Nightly News and The Today Show and having spoken at more than 200 national and international meetings.  Dr. Newman recently stepped down as the Chairman of the Duke University Department after 13 years to assume the role of PDC President.  During Dr. Newman’s tenure the department grew exponentially doubling its clinical and academic funding, and developing many outstanding individuals that have gone on to leadership roles at Duke and other key academic institutions across the country.

Smith

Peter Kent Smith

Mary and Deryl Hart Distinguished Professor of Surgery, in the School of Medicine

Dr. Smith is the Principal Investigator for the Duke site in the Cardiothoracic Surgery Clinical Trials Network (CTSN) and in recent years has focused his research efforts in clinical research. The CTSN is an NHLBI sponsored network developed to promote clinical research in cardiac surgery, and is now entering its 7th year of funding with a commitment now for an additional 5 years. Dr. Smith is the national PI for a randomized clinical trial comparing CABG alone to CABG with mitral repair for moderate ischemic mitral regurgitation. This trial is nearing completion of enrollment, and he is now the PI of a clinical trial of FFR vs angiographically guided CABG expected to begin national enrollment in September of 2013. Duke has participated as a site in 3 additional CTSN trials, and is one of two sites awarded NHLBI funding as a Clinical Skills Education Core. This funding is designed to formally develop surgical clinical trialists and promote clinical research capacity within our specialty. The Duke site has thus far sponsored 6 CTSN scholars who have all received Masters degrees in clinical research, participated in CTSN protocols and other activities of the Network. Additionally, Dr. Smith has been awarded site funding from the Veteran’s Administration to begin VA cooperative clinical research trials at the Durham VA. Through all of these activities, an integration of clinical research, publications, and scholarship with the advancement of clinically effective Thoracic Surgery is the goal.

Mathew

Joseph P. Mathew

Jerry Reves, M.D. Distinguished Professor of Cardiac Anesthesiology

Current research interests include:
1. The relationship between white matter patency, functional connectivity (fMRI) and neurocognitive function following cardiac surgery.
2. The relationship between global and regional cortical beta-amyloid deposition and postoperative cognitive decline.
3. The effect of lidocaine infusion upon neurocognitive function following cardiac surgery.
4. The association between genotype and outcome after cardiac surgery.
5. Atrial fibrillation following cardiopulmonary bypass.

Podgoreanu

Mihai V. Podgoreanu

Associate Professor of Anesthesiology

Basic-Translational:
1. Systems biology approaches to modeling perioperative cardiovascular injury and adaptation.
2. Mechanisms of perioperative myocardial injury; functional genomics applied to perioperative myocardial injury.
3. Metabolic consequences of perioperative myocardial ischemia-reperfusion injury.
4. Animal models and comparative genomic approaches to study perioperative myocardial ischemia-reperfusion injury.
5. Functional genomics of vein graft disease.
6. Animal models of vein graft disease.
7. Genetic association studies in perioperative medicine.
8. Clinico-genomic risk prediction models for perioperative and long-term adverse cardiovascular outcomes following cardiac surgery.

Clinical:
9. Intraoperative quantification of tissue perfusion by contrast echocardiography.
10. Use of myocardial tissue deformation indices to characterize perioperative ventricular dysfunction/stunning
11. 3-D echocardiographic evaluation of the right ventricle


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