Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes).

Oyunbileg Magvanjav, Caitrin W McDonough, Yan Gong, Leslie A McClure, Robert L Talbert, Richard B Horenstein, Alan R Shuldiner, Oscar R Benavente, Braxton D Mitchell, Julie A Johnson

Journal: Stroke 2017;48(5):1337-1343

PMID: 28351962

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Abstract

BACKGROUND AND PURPOSE

Functional polymorphisms (Ser49Gly and Arg389Gly) in 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 =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 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 genotype.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Address: From the Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville (O.M., C.W.M., Y.G., J.A.J.); Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA (L.A.M.); College of Pharmacy, University of Texas, Austin (R.L.T.); Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore (R.B.H., A.R.S., B.D.M.); Department of Neurology, University of British Columbia, Vancouver, Canada (O.R.B.); and Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.).; From the Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville (O.M., C.W.M., Y.G., J.A.J.); Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA (L.A.M.); College of Pharmacy, University of Texas, Austin (R.L.T.); Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore (R.B.H., A.R.S., B.D.M.); Department of Neurology, University of British Columbia, Vancouver, Canada (O.R.B.); and Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.). [email protected].

DOI: 10.1161/STROKEAHA.116.015936

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MeSH Terms: Adrenergic beta-Antagonists, Aged, Brain Ischemia, Female, Follow-Up Studies, Humans, Male, Middle Aged, Myocardial Infarction, Pharmacogenetics, Polymorphism, Genetic, Receptors, Adrenergic, beta-1, Secondary Prevention, Stroke