G Protein–Coupled Receptor Kinase 5 Gene Polymorphisms Are Associated With Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting in Patients Receiving β-Blockers

Abstract

Background We hypothesized that genetic variations in the adrenergic signaling pathway and cytochrome P450 (CYP) 2D6 enzyme are associated with new-onset atrial fibrillation (AF) in patients who underwent coronary artery bypass graft (CABG) surgery and were treated with perioperative beta-blocker (BB). Methods and Results Two cohorts of patients who underwent CABG surgery 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 CYP2D6 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 (CATHGEN) 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=0.007-0.016). However, meta-analysis of the two datasets 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). Conclusions In patients undergoing CABG surgery, genetic variation in GRK5 is associated with postoperative AF despite perioperative BB therapy.

Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery

“…In our recent candidate gene study, we found an association between variants of G protein-coupled receptor kinase 5 ( GRK5 ) gene polymorphisms and postoperative AF in the discovery and replication datasets from a subset of patients who exclusively received perioperative beta-blocker therapy. 15 In the current larger dataset, this association was still present in our discovery dataset (Supplemental Table 5), but did not reach our discovery threshold of P < 5 × 10 −5 that was required for replication in the CATHGEN cohort. This may be due to the fact that in the current study, we expanded our study cohorts to include patients with and without perioperative beta-blocker therapy.…”

“…15 Briefly, 1004 samples from the PEGASUS cohort (discovery samples) were genotyped using the Illumina Human610-Quad BeadChip.Various QC criteria were applied to ensure the genotype quality. Markers were excluded if the GenCall (http://support.illumina.com/downloads/gencall_software.html) score was ≤ 0.15, the genotype call frequency was < 98%, or gender errors were detected At the sample level, we checked cryptic relatedness and duplications.…”

Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving β-blockers

“…The parent PEGASUS study enrolled 1004 patients who underwent isolated non-emergent CABG surgery with cardiopulmonary bypass (CPB) between 1997 and 2006 [10]. The iPEGASUS study enrolled 1159 patients to study the effects of cardiothoracic surgery on the proteome, gene expression, and metabolic profile of patients undergoing cardiothoracic surgery between 2004 and 2011 using blood, plasma, and tissue from the perioperative genomics biorepositories stored in the Duke Department of Anesthesiology, Durham, North Carolina.…”

“…We recently demonstrated that genetic variation in the G protein-coupled receptor kinase 5 gene ( GRK5 ) is associated with postoperative AF in patients who underwent CABG surgery and were treated with BBs perioperatively [10]. Unfortunately, this genetic association study could not provide insight into the potential pathophysiological mechanisms associated with postoperative AF in patients treated with BBs.…”

“…Unfortunately, this genetic association study could not provide insight into the potential pathophysiological mechanisms associated with postoperative AF in patients treated with BBs. The gene expression pattern in atrial tissue, however, may help us determine the extent to which differentially expressed genes in the human atrium are associated with an increased risk for postoperative AF in CABG surgery patients, represent activities of certain biologic pathways, or predict altered response to BB therapy [10]. Further, expression quantitative trait loci (eQTL) analysis can determine the cis-/transacting effects of SNPs identified in genetic association studies, on gene expression in atrial tissue.…”