G Protein-Coupled Receptor Kinase 5 Gene Polymorphisms Are Associated with Postoperative Atrial Fibrillation Following Coronary Artery Bypass Graft Surgery in Patients Receiving Beta-Blockers
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.
- Received November 20, 2013.
- Revision received May 6, 2014.
- Accepted June 4, 2014.