title: GNAS gene variants affect β-blocker-related survival after coronary artery bypass grafting.
abstract: BACKGROUND
  Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gαs enhances inotropic responses to adrenergic stimulation and improves survival in mice under βAR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding Gαs, with the greatest Gαs protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants result in altered mortality in patients after coronary artery bypass graft surgery, particularly in those receiving βAR blockade.
  
  
  METHODS
  This prospective analysis included 1,627 European ancestry patients undergoing primary coronary artery bypass graft surgery. Patients were genotyped for two GNAS haplotype tagging single-nucleotide polymorphisms defining three major haplotypes. Up to 5-yr all-cause mortality was estimated using a Cox proportional hazard model; hazard ratios and 95% CIs were calculated while adjusting for demographics, clinical covariates, and the new EuroSCORE II.
  
  
  RESULTS
  Univariate analysis revealed haplotype-dependent 5-yr mortality rates (*1/*1: 18.9%, *2/*1: 13.7%, *2/*2: 9.3%, *3/*1: 10.6%, *3/*2: 9.1%, and *3/*3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype *1 carriers showed a doubled risk for death (hazard ratio, 2.2; 95% CI, 1.2 to 3.8; P = 0.006). Considering only patients receiving βAR blockers (n = 1,267), the adjusted risk of death even tripled (hazard ratio, 3.0; 95% CI, 1.5 to 6.1; P = 0.002).
  
  
  CONCLUSIONS
  GNAS haplotypes independently associate with an increased risk of death after primary coronary artery bypass graft surgery. These results are most pronounced in patients receiving βAR blockers, strengthening the rationale for personalized treatment, to decrease medication side effects and improve outcomes.
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Frey
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Jochen D
authors.initials: JD
authors.lastname: Muehlschlegel
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Ochterbeck
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Fox
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Stanton K
authors.initials: SK
authors.lastname: Shernan
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Charles D
authors.initials: CD
authors.lastname: Collard
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Jürgen
authors.initials: J
authors.lastname: Peters
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (U.H.F., C.O., J.P.); Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.M., S.K.S., S.B.); Department of Anesthesiology and Pain Management, Southwestern Medical Center, Dallas, Texas (A.A.F.); Division of Cardiovascular Anesthesiology, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston Texas (C.D.C.); and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany (P.L.).
authors.forename: Simon
authors.initials: S
authors.lastname: Body
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002864:Chromogranins; D015331:Cohort Studies; D001026:Coronary Artery Bypass / Q000009:adverse effects / Q000401:mortality*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012042:Registries; D015996:Survival Rate / Q000639:trends; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
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