TY - JOUR
T1 - Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms with Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)
AU - NINDS SiGN (Stroke Genetics Network)
AU - Magvanjav, Oyunbileg
AU - McDonough, Caitrin W.
AU - Gong, Yan
AU - McClure, Leslie A.
AU - Talbert, Robert L.
AU - Horenstein, Richard B.
AU - Shuldiner, Alan R.
AU - Benavente, Oscar R.
AU - Mitchell, Braxton D.
AU - Johnson, Julie A.
N1 - Funding Information:
This project was supported by funding from the National Institutes of Health's National Institute of Neurological Disorders and Stroke (Grants R01 NS073346, U01 NS038529, and U01 NS069208), National Institute for General Medical Sciences (U01 GM074492), and National Institute for Diabetes, Kidney, and Digestive Disorders (P30 DK072488).
Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Background and Purpose - Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and β-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by β-blocker treatment in patients with a history of stroke. Methods - Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). Results - MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, β-blocker-treated Gly49 carriers had increased MACE versus non-β-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. Conclusion - Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among β-blocker-treated individuals. Further research is needed to define β-blocker benefit among ischemic stroke patients by ADRB1 genotype.
AB - Background and Purpose - Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and β-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by β-blocker treatment in patients with a history of stroke. Methods - Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). Results - MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, β-blocker-treated Gly49 carriers had increased MACE versus non-β-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. Conclusion - Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among β-blocker-treated individuals. Further research is needed to define β-blocker benefit among ischemic stroke patients by ADRB1 genotype.
KW - ADRB1
KW - Ser49Gly
KW - cardiovascular disease
KW - pharmacogenetics
KW - stroke
KW - β-blockers
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U2 - 10.1161/STROKEAHA.116.015936
DO - 10.1161/STROKEAHA.116.015936
M3 - Article
C2 - 28351962
AN - SCOPUS:85016391633
SN - 0039-2499
VL - 48
SP - 1337
EP - 1343
JO - Stroke
JF - Stroke
IS - 5
ER -