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

Abstract

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.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Keywords: ADRB1; Ser49Gly; cardiovascular disease; pharmacogenetics; stroke; β-blockers.

© 2017 American Heart Association, Inc.

Figures

Figure 1

Cumulative incidence of MACE by Ser49Gly genotype among hypertensive participants in SPS3-GENES, N=926 MACE (Major Adverse Cardiovascular Events): stroke, myocardial infarction, all-cause death; 75% of events were ischemic stroke

Figure 2

Cumulative incidence of MACE among Gly49 allele carriers treated with β-blockers compared to other groups* in SPS3-GENES, N=926 MACE (Major Adverse Cardiovascular Events): stroke, myocardial infarction, all-cause death; 75% of events were ischemic stroke *‘Other groups’ included Gly49 allele carriers not treated with β-blockers and non-carriers (Ser49Ser) regardless of β-blocker treatment