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Original Articles

Variation in the 4q25 Chromosomal Locus Predicts Atrial Fibrillation After Coronary Artery Bypass Graft Surgery

Simon C. Body, MBChB, MPH; Charles D. Collard, MD; Stanton K. Shernan, MD; Amanda A. Fox, MD; Kuang-Yu Liu, PhD; Marylyn D. Ritchie, PhD; Tjörvi E. Perry, MD, MMSc; Jochen D. Muehlschlegel, MD; Sary Aranki, MD; Brian S. Donahue, MD, PhD; Mias Pretorius, MBChB; Juan-Carlos Estrada, MD; Patrick T. Ellinor, MD, PhD; Christopher Newton-Cheh, MD, MPH; Christine E. Seidman, MD; J.G. Seidman, PhD; Daniel S. Herman;; Peter Lichtner, PhD; Thomas Meitinger, MD; Arne Pfeufer, MD; Stefan Kääb, MD; Nancy J. Brown, MD; Dan M. Roden, MD and Dawood Darbar, MD

From the Department of Anesthesiology, Perioperative and Pain Medicine (S.C.B., S.K.S., A.A.F., K.-Y.L., T.E.P., J.D.M.), Division of Cardiac Surgery (S.A.), Howard Hughes Medical Institute (C.E.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Baylor College of Medicine, Division of Cardiovascular Anesthesia at the Texas Heart Institute (C.D.C.), Saint Luke’s Episcopal Hospital, Houston, Tex; Departments of Anesthesiology (B.S.D., M.P.), Medicine (J.-C.E., D.M.R., N.J.B., D.D.), and Pharmacology (N.J.B., D.M.R.), and Center for Human Genetics Research (M.D.R.), Vanderbilt University School of Medicine, Nashville, Tenn; Department of Genetics (J.G.S., C.E.S., D.S.H.) and the Harvard Medical School—Partners HealthCare Center for Genetics and Genomics (J.G.S.), Harvard Medical School, Boston, Mass; Cardiovascular Research Center (P.T.E., C.N.-C.) and Center for Human Genetic Research (C.N.-C.), Massachusetts General Hospital, Boston, Mass; Program in Medical and Population Genetics (C.N.-C.), Broad Institute of Harvard and MIT, Boston, Mass; Institute of Human Genetics (T.M., P.L., A.P., S.K.), Helmholtz Zentrum München, Neuherberg, and Institute of Human Genetics, Technische Universität München, Munich, Germany; and Medizinische Klinik (S.K.), Klinikum der Universität München–Grosshadern, Munich, Germany.

Correspondence to Simon C. Body, MBChB, MPH, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail body{at}zeus.bwh.harvard.edu

Received January 5, 2009; accepted July 15, 2009.

Background— Atrial fibrillation (AF) is the most common adverse event following coronary artery bypass graft surgery. A recent study identified chromosome 4q25 variants associated with AF in ambulatory populations. However, their role in postoperative AF is unknown. We hypothesized that genetic variants in the 4q25 chromosomal region are independently associated with postoperative AF after coronary artery bypass graft surgery.

Methods and Results— Two prospectively collected cohorts of patients undergoing coronary artery bypass graft surgery, with or without concurrent valve surgery, at 3 US centers. From a discovery cohort of 959 patients, clinical and genomic multivariate predictors of postoperative AF were identified by genotyping 45 single-nucleotide polymorphisms (SNPs) encompassing the 4q25 locus. Three SNPs were then assessed in a separately collected validation cohort of 494 patients. After adjustment for clinical predictors of postoperative AF and multiple comparisons, rs2200733, rs13143308, and 5 other linked SNPs independently predicted postoperative AF in the discovery cohort. Additive odds ratios for the 7 associated 4q25 SNPs ranged between 1.57 and 2.17 (P=8.0x10^–4 to 3.4x10^–6). Association with postoperative AF were measured and replicated for rs2200733 and rs13143308 in the validation cohort.

Conclusions— In 2 independently collected cardiac surgery cohorts, noncoding SNPs within the chromosome 4q25 region are independently associated with postoperative AF after coronary artery bypass graft surgery after adjusting for clinical covariates and multiple comparisons.

Key Words: atrial fibrillation • arrhythmia • postoperative complication • heart surgery • genetics

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CLINICAL PERSPECTIVE

Guest Editor for this article was Arthur J. Moss, MD.

The study is registered at ClinicalTrials.gov (http://clinicaltrials.gov/show/NCT00281164).

The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.109.849075.