title: Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving β-blockers.
abstract: Atrial tissue gene expression profiling may help to determine how differentially expressed genes in the human atrium before cardiopulmonary bypass (CPB) are related to subsequent biologic pathway activation patterns, and whether specific expression profiles are associated with an increased risk for postoperative atrial fibrillation (AF) or altered response to β-blocker (BB) therapy after coronary artery bypass grafting (CABG) surgery. Right atrial appendage (RAA) samples were collected from 45 patients who were receiving perioperative BB treatment, and underwent CABG surgery. The isolated RNA samples were used for microarray gene expression analysis, to identify probes that were expressed differently in patients with and without postoperative AF. Gene expression analysis was performed to identify probes that were expressed differently in patients with and without postoperative AF. Gene set enrichment analysis (GSEA) was performed to determine how sets of genes might be systematically altered in patients with postoperative AF. Of the 45 patients studied, genomic DNA from 42 patients was used for target sequencing of 66 candidate genes potentially associated with AF, and 2,144 single-nucleotide polymorphisms (SNPs) were identified. We then performed expression quantitative trait loci (eQTL) analysis to determine the correlation between SNPs identified in the genotyped patients, and RAA expression. Probes that met a false discovery rate<0.25 were selected for eQTL analysis. Of the 17,678 gene expression probes analyzed, 2 probes met our prespecified significance threshold of false discovery rate<0.25. The most significant probe corresponded to vesicular overexpressed in cancer - prosurvival protein 1 gene (VOPP1; 1.83 fold change; P=3.47×10(-7)), and was up-regulated in patients with postoperative AF, whereas the second most significant probe, which corresponded to the LOC389286 gene (0.49 fold change; P=1.54×10(-5)), was down-regulated in patients with postoperative AF. GSEA highlighted the role of VOPP1 in pathways with biologic relevance to myocardial homeostasis, and oxidative stress and redox modulation. Candidate gene eQTL showed a trans-acting association between variants of G protein-coupled receptor kinase 5 gene, previously linked to altered BB response, and high expression of VOPP1. In patients undergoing CABG surgery, RAA gene expression profiling, and pathway and eQTL analysis suggested that VOPP1 plays a novel etiological role in postoperative AF despite perioperative BB therapy.
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: miklos.kertai@duke.edu.
authors: Miklos D
authors: MD
authors: Kertai
authors: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA.
authors: Wenjing
authors: W
authors: Qi
authors: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA; Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors: Yi-Ju
authors: YJ
authors: Li
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA.
authors: Frederick W
authors: FW
authors: Lombard
authors: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA 30912.
authors: Yutao
authors: Y
authors: Liu
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA.
authors: Michael P
authors: MP
authors: Smith
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA.
authors: Mark
authors: M
authors: Stafford-Smith
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA.
authors: Mark F
authors: MF
authors: Newman
authors: Department of Surgery, Division of Cardiothoracic Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors: Carmelo A
authors: CA
authors: Milano
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA.
authors: Joseph P
authors: JP
authors: Mathew
authors: Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Durham, NC 27710, USA.
authors: Mihai V
authors: MV
authors: Podgoreanu
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000368:Aged; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D001026:Coronary Artery Bypass; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011184:Postoperative Period; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000319:Adrenergic beta-Antagonists; D014157:Transcription Factors; C500380:VOPP1 protein, human; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human
keywords: Atrial fibrillation; Beta-blocker, gene expression; Coronary artery bypass graft; G protein-coupled receptor kinase 5; Human atrial tissue; Myocardial homeostasis; Overexpressed in cancer; Oxidant stress; Redox modulation; Survival protein 1; Vesicular