β-Adrenergic Receptor Gene Polymorphisms and β-Blocker Treatment Outcomes in Hypertension

Abstract

Numerous studies have demonstrated that β 1 -and β 2 -adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and β-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI ), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR )-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR ) 3.66, 95% confidence interval (95% CI) 1. 68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the β-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and β-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.Cardiovascular disease is the leading cause of morbidity and mortality in the United States. 1 Evidence is accumulating that genetic polymorphisms may be predictive of cardiovascular risk. 2,3 Moreover, several studies have identified genetic factors that influence blood pressure and metabolic responses to β-blockers, thiazide diuretics, and renin-angiotensin system antagonists. 4 Whether such pharmacogenetic differences translate to differences in the clinical outcome of antihypertensive therapy is less clear, particularly when patients receive multiple drugs that are titrated to a target blood pressure. 5 A pharmacogenetic approach to treating hypertension could not only reduce the number and cost of medications but also reduce morbidity and mortality if the outcome of drug treatment differs by genotype.Single-nucleotide polymorphisms (SNPs) in the genes encoding the adrenergic receptors have functional and physiological consequences. 6 β 1 -adrenergic receptors are important in Correspondence: JA Johnson (E-mail: johnson@cop.ufl.edu). Taken together, genetically determined differences in β-adrenergic receptor function may influence cardiovascular risk as well as the degree of risk reduction conferred by drugs that inhibit adrenergic activity. Therefore, we investigated the influence of ADRB1 and ADRB2 haplotype variation on the incidence of death, nonfatal myocardial infarction (MI), and nonfatal stroke as well as the pharmacogenetics of β-blocker-and calcium channel blocker-based antihypertensive therapy in the INternational VErapamil SR/Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Based on the literature, we hypothesized that patients with the ADRB1 Ser49-Arg389 haplotype or the ADRB2 haplotype containing the Arg16 and Gln27 alleles would be at relatively higher risk for cardiovascular events 11,12 and that atenolol would be beneficial as ...

S49G and R389G polymorphisms of the β1-adrenergic receptor influence signaling via the cAMP-PKA and ERK pathways

“…This is important for two reasons. First, glycine is the minor allele at both loci, but there are important racial (14,22). Hence, while the results of this and previous studies in reductionist models that characterize the signaling properties of the S49G polymorphism on a G 389 background are of interest from a theoretical standpoint, the physiological relevance of these findings will require further study.…”

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…However, if patients with this haplotype were treated with atenolol, their mortality risk increased by 2-fold only compared with the other haplotypes, a nominal increase that was not significant. Polymorphisms in ADRB2 had no conclusive effects (Tables 6 and 7) (Pacanowski et al, 2008). Together, this would favor a concept where ␤-blocker therapy could abolish risks induced by ␤ 1 -AR variants.…”

“…The case for an effect of ␤ 2 -AR SNPs on susceptibility to agonist-induced desensitization is more convincing; however, its clinical relevance for agonist use in cardiovascular medicine remains unclear because such drugs typically are not administered long term. When such agonists are used long term in pulmonary medicine and exhibit cardiovascular side effects, the role of polymorphisms affecting desensitization also remains unclear in light of the frequent concomitant administra- No difference in event rates Pacanowski et al, 2008 524 tion with glucocorticoids, which can counteract agonistinduced ␤ 2 -AR desensitization (Postma et al, 2008).…”

Evidences for oxidative stress in essential hypertension

“…The possible explanation could be also find in association between certain clonidine. An emerging consensus from these studies is that single gene effects on antihypertensive drug responses are small, and even the combined effects of all presently known polymorphisms do not account for enough variation in response to be clinically useful [19][20][21][22]. Endothelial dysfunction has been previously documented in patients with essential hyper tension [17,18,23] and, together with advanced atherosclerotic process, it could be the reason of lower drug effect within a group with non regulated hypertension.…”