TY - JOUR
T1 - GNAS gene variants affect β-blocker-related survival after coronary artery bypass grafting
AU - Frey, Ulrich H.
AU - Muehlschlegel, Jochen D.
AU - Ochterbeck, Christoph
AU - Fox, Amanda A.
AU - Shernan, Stanton K.
AU - Collard, Charles D.
AU - Lichtner, Peter
AU - Peters, Jürgen
AU - Body, Simon
PY - 2014/5
Y1 - 2014/5
N2 - Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gás 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 Gás, with the greatest Gás 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%, and3/3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype1 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 β AR 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.
AB - Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gás 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 Gás, with the greatest Gás 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%, and3/3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype1 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 β AR 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.
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U2 - 10.1097/ALN.0000000000000189
DO - 10.1097/ALN.0000000000000189
M3 - Article
C2 - 24755784
AN - SCOPUS:84899093946
SN - 0003-3022
VL - 120
SP - 1109
EP - 1117
JO - Anesthesiology
JF - Anesthesiology
IS - 5
ER -