Amino-acid changing SNPs in the adrenergic receptors have previously been shown to be associated with cardiovascular and drug response phenotypes. In treated hypertensive patients with CAD, we identified a significant association between SNPs in ADRB1
and the incidence of all-cause death, showing that patients with haplotypes bearing the common alleles (Ser49 and Arg389) were at relatively higher risk. The risk associated with this haplotype was significantly reduced by β-blocker therapy, but not by calcium channel blocker therapy, a finding consistent with the understanding of the functional consequences of these genetic polymorphisms. Specifically, the Arg389 form of the receptor has been documented in several in vitro
and ex vivo
studies to be associated with increased coupling of the β1
-adrenergic receptor to G protein, leading to greater adenylyl cyclase activation.17,18
The Ser49 form of the receptor has most consistently been associated with resistance to receptor downregulation.19,20
Therefore, the Ser49-Arg389 haplotype would be expected to be most responsive to activation by catecholamines, and consequently a greater response to β-blockade with this haplotype would also be expected.
Consistent with our primary hypothesis, patients with at least one copy of the haplotype containing the wild-type Ser49 and Arg389 alleles were at relatively higher risk for the primary outcome than patients with variant alleles. The main haplotype association was driven by more than a threefold difference in the rate of all-cause mortality.21
Our findings are in line with those of Iwai et al
who reported an association between the Arg389 allele and MI, but other observational studies have not supported a major influence of ADRB1
variants on cardiovascular risk.12,23
The lack of consistency may be attributable to differences in patient populations studied (i.e., those with or without overt CAD)23
or prevalent use of β-blockers.12
Our data support the use of β-blockers as being a potential confounder for detecting the genetic association with outcomes, given that there were no differences in outcomes by genotype among the atenolol-treated patients. Overall, the results of the current investigation are in line with the known functionality of these variants and the widely recognized adverse consequences of chronic sympathetic activation.
The pharmacogenetic findings regarding the Ser49-Arg389 haplotype are consistent not only with the in vitro
and ex vivo
studies documenting the functional basis of these polymorphisms but also with the existing β-blocker pharmacogenetics literature. 24,25
This study extends those findings to include outcomes of antihypertensive therapy. In our investigation, patients carrying the Ser49-Arg389 haplotype derived a significant survival benefit from the use of a β-blocker. We previously demonstrated that hypertensive patients who were Ser49-Arg389 homozygotes experienced a significantly greater blood pressure response to β-blockers than those with haplotypes containing a variant allele.13
With variations on this theme, four other studies have corroborated the finding that patients with the Arg389 allele or Ser49-Arg389 haplotype show a greater blood pressure response to β-blockers.8,14,26,27
It follows that, in certain subpopulations, hypertension may have a strong adrenergic component that is particularly amenable to β-blocker therapy. Similarly, studies in heart failure patients have also suggested the Arg389 allele or Ser49-Arg389 haplotype is associated with the greatest improvement in ejection fraction after initiation of β-blocker therapy.15,28,29
Liggett et al
. recently demonstrated that Arg389 homozygous heart failure patients derived a significant survival benefit from bucindolol as compared with placebo, whereas in Gly389 carriers the outcomes with bucindolol and placebo were similar.30
Taken together, these studies suggest that the ADRB1 gene is an important pharmacogenetic target for β-blocker response. The literature suggests that polymorphisms in the gene influence intermediate-response phenotypes (e.g., blood pressure reduction and ejection fraction improvement) along with mortality outcomes in hypertension and heart failure. The specific findings from this study suggest that β-blockers may be the preferred antihypertensive therapy in hypertensive CAD patients who are Ser49-Arg389 carriers.
It should be noted that carriers of the major alleles (Ser49 and Arg389) were at relatively increased risk and benefited from β-blocker therapy, and, conversely, those with a variant on both chromosomes were at lower risk. This is in contrast to the apparent inheritance patterns of some of the other β-blocker pharmacogenetics studies for ADRB1
described above, in which a dominant model was typically assumed, with Ser49-Arg389 homozygotes exhibiting the greatest β-blocker response and carriers of at least one variant allele/haplotype having a lesser response. However, very few studies have been sufficiently powered to test for mode of inheritance, given that variant homozygotes, typically, have been minimally represented. In these cases a dominant model (whereby variant carriers were often collapsed to a single group) was typically pursued out of statistical necessity. Thus, although the mode of inheritance of this association seems to be in contrast to some of the β-blocker pharmacogenetics literature, it can also be concluded that the literature has not revealed a clear pattern of inheritance for this gene and the resulting phenotypes. This is the largest ADRB1
pharmacogenetic study to date and, from this perspective, may have been the best powered to assess for mode of inheritance. Additionally, with complex phenotypes, it is possible that different phenotypes will exhibit different inheritance patterns.15,30
We also identified a statistical interaction between atenolol and verapamil SR and ADRB2 haplotypes. However, this did not meet our threshold for significance after adjusting for multiple comparisons. This association was driven primarily by divergent risks for both death and nonfatal MI, and none of the associations appeared to be driven by differences in blood pressure. If the findings for ADRB2 are validated, knowledge of this haplotype may further enhance the ability to identify patients who might benefit from β-blocker therapy.
As a cohort study nested in a randomized trial with adjudicated end points, INVEST-GENES has several advantages over population-based studies, and the results are generalizable to other CAD populations managed with contemporary interventions. However, the current investigation also has limitations that deserve consideration. First, despite the large size of the study population, the event rate was low, and this study may have been underpowered to evaluate gene–drug interactions, particularly for the individual end points and within certain subgroups of patients (i.e., individual end point by drug by gene by race). Second, the INVEST-GENES population is racially/ ethnically diverse. To control for potential confounding by population stratification, we considered analyses separately by race and by inclusion of ancestry informative marker data. These various analyses suggest that our findings are not confounded by population stratification. Third, the use of trandolapril and hydrochlorothiazide was, by design, different in the two treatment strategies and may have influenced the results. However, the findings were similar in the expanded model that adjusted for exposure to these drugs. Last, replication in independent cohorts is desirable. In the absence of another study with randomized drug therapy and comparably rigorous follow-up and phenotype definition, we must rely on the existing evidence from the laboratory and endophenotype studies.31
Identifying genetic markers for cardiovascular risk has the potential to improve cardiovascular risk stratification and identify those requiring more aggressive management of hypertension and related chronic diseases. Common SNPs in the genes encoding the β1- and β2-adrenergic receptors alter receptor activity and have physiological consequences. Consistent with the known functionality of the β1-adrenergic receptor variants, we identified an association between ADRB1 haplotypes and the risk of death. More importantly, our data suggest that β-blockers offset this mortality risk, in keeping with observations that patients bearing the wild-type alleles are more responsive to β-blocker therapy in settings of blood pressure lowering, improvement in ejection fraction, and survival in heart failure. ADRB2 variants were similarly associated with treatment outcomes, but given the inconsistencies in the literature, these findings require independent replication. The pharmacogenetic evidence for β-blockers and adrenergic receptor genes is highly convincing, particularly for ADRB1, and our data suggest that a patient’s genotype could influence the antihypertensive drug choice independent of blood pressure responses.