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 926 participants of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial’s 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 Stroke Genetics Network (SiGN). Results MACE was higher in carriers of the Gly49 allele than those with the Ser49Ser genotype (10.5% vs. 5.4%, log-rank p=0.005). Gly49 carrier status was associated with MACE (HR 1.62; 95% CI 1.00–2.68) and ischemic stroke (HR 1.81; 95% CI 1.01–3.23) in SPS3 and with small artery ischemic stroke (OR 1.14; 95% CI 1.03–1.26) in SiGN. In SPS3, β-blocker-treated Gly49 carriers had increased MACE versus non-β-blocker-treated individuals and non-carriers (HR 2.03; 95% CI 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.

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…In patients with minor ischemic stroke, platelet receptor gene (P2Y12 and P2Y1) and glycoprotein gene (GPIIIa) polymorphisms influence antiplatelet drug responsiveness and clinical outcomes [329], and there are genetic differences (rs12143842) in the response of stroke patients to antihypertensive drugs (chlorthalidone, amlodipine, or lisinopril), especially regarding HNRNPA1P4 and NOS1AP variants in African Americans and PRICKLE1 and NINJ2 variants in non-Hispanic Whites [330].…”

Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Control in Hypertension

“…Currently, BP response to beta-blockers has focused primarily on genetic variants of ADRB1 and ADRB2 . Specifically, the Ser49 and Arg389 of ADRB1 ( rs1801252 and rs1801253 respectively) and the Arg16 and Glu27 of ADRB2 ( rs1042713 and rs1042714 respectively) have demonstrated improved responsiveness to and decreased adverse event risk and mortality with beta-blockade [31,32,33,37,38].…”

“…Furthermore, genotype association studies have demonstrated improved clinical outcomes when the functional genotype is taken into consideration [11,12,16,24]. These clinical outcomes include: improved K + and Cl − excretion, decreased adverse events (myocardial infarction, stroke, coronary heart disease) and decreased mortality risk [37,38,39,40,41]. Despite the clear promise of genetically-guided therapy for BP control, clinical care settings are slow to adopt this approach.…”

Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment

“…that Gly49 individuals should preferentially receive CCB therapy. However, this recommendation would be corroborated by recent results from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, in which individuals with the ADRB1 Gly49 allele who were treated with atenolol were at higher risk for major adverse cardiovascular events (hazard ratio 2.03; 95% CI 1.20–3.45) [63].…”