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G protein-coupled receptor kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary artery bypass grafting in patients receiving ?-blockers.

ABSTRACT: We hypothesized that genetic variations in the adrenergic signaling pathway and cytochrome P450 2D6 enzyme are associated with new-onset atrial fibrillation (AF) in patients who underwent coronary artery bypass grafting and were treated with perioperative ?-blockers (BBs).Two cohorts of patients who underwent coronary artery bypass grafting and received perioperative BBs at Duke University Medical Center were studied. In a discovery cohort of 563 individuals from the Perioperative Genetics and Safety Outcomes Study (PEGASUS), using a covariate-adjusted logistic regression analysis, we tested 492 single-nucleotide polymorphisms (SNPs) in 10 candidate genes of the adrenergic signaling pathway and cytochrome P450 2D6 for association with postoperative AF despite perioperative BB therapy. SNPs meeting a false discovery rate ?0.20 (P<0.002) were then tested in the replication cohort of 245 individuals from the Catheterization Genetics biorepository. Of the 492 SNPs examined, 4 intronic SNPs of the G protein-coupled kinase 5 (GRK5) gene were significantly associated with postoperative AF despite perioperative BB therapy in the discovery cohort with additive odds ratios between 1.72 and 2.75 (P=4.78×10(-5) to 0.0015). Three of these SNPs met nominal significance levels in the replication cohort with odds ratios between 2.07 and 2.60 (P=0.007 to 0.016). However, meta-analysis of the 2 data sets cohorts suggested strong association with postoperative AF despite perioperative BB therapy in all 4 SNPs (meta-P values from 1.66×10(-6) to 3.39×10(-5)).In patients undergoing coronary artery bypass grafting, genetic variation in GRK5 is associated with postoperative AF despite perioperative BB therapy.

SUBMITTER: Kertai MD

PROVIDER: S-EPMC4270923 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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G protein-coupled receptor kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary artery bypass grafting in patients receiving β-blockers.

Kertai Miklos D MD Li Yen-Wei YW Li Yi-Ju YJ Shah Svati H SH Kraus William E WE Fontes Manuel L ML Stafford-Smith Mark M Newman Mark F MF Podgoreanu Mihai V MV Mathew Joseph P JP

Circulation. Cardiovascular genetics 20140721 5

<h4>Background</h4>We hypothesized that genetic variations in the adrenergic signaling pathway and cytochrome P450 2D6 enzyme are associated with new-onset atrial fibrillation (AF) in patients who underwent coronary artery bypass grafting and were treated with perioperative β-blockers (BBs).<h4>Methods and results</h4>Two cohorts of patients who underwent coronary artery bypass grafting and received perioperative BBs at Duke University Medical Center were studied. In a discovery cohort of 563 in ...[more]

PMID: 25049040

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Project description: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.

Project description:Background The CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke or TIA [transient ischemic attack], vascular disease, age 65 to 74 years, sex category female; 2 indicates 2 points, otherwise 1 point) scoring system is recommended to guide decisions on oral anticoagulation therapy for stroke prevention in patients with nonsurgery atrial fibrillation. A score ≥1 in men and ≥2 in women, corresponding to an annual stroke risk exceeding 1%, warrants long-term oral anticoagulation provided the bleeding risk is acceptable. However, in patients with new-onset postoperative atrial fibrillation, the optimal risk stratification method is unknown. The aim of this study was therefore to evaluate the CHA2DS2-VASc scoring system for estimating the 1-year ischemic stroke risk in patients with new-onset postoperative atrial fibrillation after coronary artery bypass grafting. Methods and Results All patients with new-onset postoperative atrial fibrillation and without oral anticoagulation after first-time isolated coronary artery bypass grafting performed in Sweden during 2007 to 2017 were eligible for this registry-based observational cohort study. The 1-year ischemic stroke rate at each step of the CHA2DS2-VASc score was estimated using a Kaplan-Meier estimator. Of the 6368 patients included (mean age, 69.9 years; 81% men), >97% were treated with antiplatelet drugs. There were 147 ischemic strokes during the first year of follow-up. The ischemic stroke rate at 1 year was 0.3%, 0.7%, and 1.5% in patients with CHA2DS2-VASc scores of 1, 2, and 3, respectively, and ≥2.3% in patients with a score ≥4. A sensitivity analysis, with the inclusion of patients on anticoagulants, was performed and supported the primary results. Conclusions Patients with new-onset atrial fibrillation after coronary artery bypass grafting and a CHA2DS2-VASc score <3 have such a low 1-year risk for ischemic stroke that oral anticoagulation therapy should probably be avoided.

Project description:BackgroundPostoperative atrial fibrillation (POAF) is the most common cardiac dysrhythmia to occur after coronary artery bypass grafting (CABG). However, the risk factors for new-onset POAF after CABG during the perioperative period have yet to be clearly defined. Accordingly, the aim of our systematic review was to evaluate the perioperative predictors of new-onset POAF after isolated CABG.MethodOur review methods adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We searched seven electronic databases (PubMed, Embase, CINAHL, PsycArticles, Cochrane, Web of Science, and SCOPUS) to identify all relevant English articles published up to January 2020. Identified studies were screened independently by two researchers for selection, according to predefined criteria. The Newcastle-Ottawa Scale was used to evaluate the quality of studies retained.ResultsAfter screening, nine studies were retained for analysis, including 4798 patients, of whom 1555 (32.4%) experienced new-onset POAF after CABG. The incidence rate of new-onset POAF ranged between 17.3% and 47.4%. The following risk factors were identified: old age (p < 0.001), a high preoperative serum creatinine level (p = 0.001), a low preoperative hemoglobin level (p = 0.007), a low left ventricle ejection fraction in Asian patients (p = 0.001), essential hypertension (p < 0.001), chronic obstructive pulmonary disease (p = 0.010), renal failure (p = 0.009), cardiopulmonary bypass use (p = 0.002), perfusion time (p = 0.017), postoperative use of inotropes (p < 0.001), postoperative renal failure (p = 0.001), and re-operation (p = 0.005). All studies included in the analysis were of good quality.ConclusionsThe risk factors identified in our review could be used to improve monitoring of at-risk patients for early detection and treatment of new-onset POAF after CABG, reducing the risk of other complications and negative clinical outcomes.

Dataset Information

G protein-coupled receptor kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary artery bypass grafting in patients receiving ?-blockers.

Publications

G protein-coupled receptor kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary artery bypass grafting in patients receiving β-blockers.

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