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European Journal of Heart Failure 2003 5(4):463-468; doi:10.1016/S1388-9842(03)00044-8
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© 2003 European Society of Cardiology

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study

On behalf of the MERIT-HF Study Group, Hazel L. Whitea,*, Rudolf A. de Boerb, Azhar Maqboola, Darren Greenwooda, Dirk J. van Veldhuisenb, Richard Cuthberta, Stephen G. Balla, Alistair S. Halla and Anthony J. Balmfortha

a Institute for Cardiovascular Research University of Leeds, Leeds, UK
b Department of Cardiology, University Hospital Groningen Groningen, The Netherlands

* Corresponding author. Tel.: +44-113-233-4807; fax: +44-113-392-5405 E-mail address: hlwhite{at}doctors.org.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The Glycine389 variant of the beta-1 adrenergic receptor (β1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant.

Aims: The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers.

Methods: We identified the genotype at amino acid 389 of the β1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes.

Results: The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69–1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44–0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL.

Conclusion: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.

Key Words: Beta-1 adrenergic receptor • Polymorphism • Heart failure

Received November 21, 2002; Revised January 29, 2003; Accepted March 20, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The sympathetic nervous system has been unequivocally linked to the development and progression of cardiovascular disease [1]. Congestive heart failure (CHF) is a condition in which sympathetic activity is greatly enhanced. The beta-1 adrenergic receptor (β1AR) mediates the adverse effects of these excess catecholamines by increasing oxygen demand, wall tension, myocyte necrosis and apoptosis [2–4]. Furthermore, β1AR stimulation is arrhythmogenic; several electrophysiological mechanisms having been proposed [5]. Finally, β1AR stimulation promotes arterial flow aberrations/pressure related wall stress, favouring endothelial injury and plaque rupture [6,7]. The clinical importance of the function of this receptor is demonstrated by the therapeutic response to beta blockade in patients with heart failure [8,9]. In MERIT-HF a risk reduction of 34% in the incidence of the primary endpoint, all-cause mortality, was seen in those on Metoprolol CR/XL treatment [8].

The β1AR is a member of the adrenergic family of membrane-bound G protein coupled receptors. The GTP binding protein (G protein) interacts with the intracellular domains of the receptor, and following agonist binding, dissociates from the receptor and stimulates adenylate cyclase to generate cAMP. This activates various intracellular processes including the influx of calcium through L-type calcium channels resulting in cardiac ionotropy and chronotropy [10]. The Arg389Gly polymorphism results in the substitution of the amino acid, arginine by glycine, at a critical site for G protein coupling (Fig. 1). Recently, in a biochemical model (in vitro) it has been demonstrated that the cAMP signal produced by the more common arginine form (Arg389), is threefold that of the Glycine (Gly389) [11]. Arg389 therefore, could be termed the more active form of the receptor. Alternatively it could be argued that individuals possessing the less common, Gly389 are naturally ‘beta-blocked’. Not only could this natural beta blockade affect the propensity to develop CHF but this polymorphism could also account for some of the inter-individual variability observed in the natural history of cardiovascular disease and such a functional variant would be predicted to influence mortality in CHF. The favourable effect of beta-blockers on morbidity and mortality in chronic heart failure provides rationale for a protective effect of the ‘less active’ Gly389 receptor. We therefore hypothesised that the Arg389Gly polymorphism of the human β1AR may be an important determinant of adverse events (death/hospitalisation) in heart failure.


Figure 1
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  		Fig. 1 The two amino acid changing polymorphisms of the human β1AR.

 
Furthermore, this polymorphism may be one of potentially several genetic loci enabling the provision of more appropriate and individualized therapy in heart failure. Inter-individual variation in therapeutic efficacy has been observed in the clinical use of beta-blockers [12]. We hypothesised that those individuals possessing the more active Arg389 form of the receptor may manifest a comparatively greater physiological response to beta-1 selective blockade and benefit relatively more from the protective effects of beta-antagonists than those with the naturally beta-blocked Gly389 variant. Therefore, a pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study design
In the MERIT-HF Study, 3991 patients with chronic heart failure (NYHA class II–IV) were randomly assigned to Metoprolol CR/XL once daily (eventual target dose 200 mg) or placebo [8]. Dose regimen could be modified according to the judgement of the investigator. If a patient did not tolerate an increase in dose, temporary decrease in study drug or increase in diuretic dose was recommended. The international steering committee stopped the study after a mean follow-up period of 1 year on the recommendation of the independent safety committee. The predefined criterion for ending the study had been met and exceeded.

We obtained ethical approval from the local regional ethics committees to identify the β1AR Arg389Gly genotype in the UK and Dutch participants (n=718). The events were recorded within the framework of the MERIT-HF. For the analysis in this sub-study we used the combined endpoint of all-cause mortality or hospitalisation. Patients with an endpoint were assigned to the event group, those without, to the non-event group. Baseline characteristics were recorded at the screening visit. Resting heart rate and blood pressure were recorded at baseline and at every subsequent clinic visit as the study drug was increased. This investigation conforms with the principles outlined in the declaration of Helsinki.

2.2. Determination of Arg389Gly genotype
DNA was extracted successfully from a frozen venous blood sample collected from 600 patients following up-titration of individual therapy (on the approximate 90 day follow-up visit). DNA was not obtained from the remaining 118 patients. In 72 of these patients, this was because a blood sample was never obtained during the study. In 12 patients death occurred prior to proposed venesection. For the remainder, the blood sample was inadequate to permit DNA analysis (34 patients). Each individual was genotyped for the Arg389Gly polymorphism using a modification of an assay previously described [13]. Briefly, a 530 bp fragment containing the polymorphic site was amplified by PCR. The Arg389 allele PCR product contains a unique site for restriction by Bcg1, thus cleavage of the 530 bp fragment into fragments of 342 and 154 bp confirms the presence of this allele (Fig. 2). The fragments were separated by gel electrophoresis on an 8% polyacylamide gel, stained with ethidium bromide and visualised under UV light.


Figure 2
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  		Fig. 2 Genotyping of Arg389Gly polymorphism. PCR products were digested with Bcg1. Restriction enzyme and products were separated by electrophoresis on an 8% polyacrylamide gel. AA, ArgArg; AG, ArgGly; GG, GlyGly.

 
2.3. Statistical analysis
Cox regression analysis was used to calculate risk-ratios (RRs) with 95% confidence intervals (CI) for each genotype. Kaplan–Meier survival curves were constructed. The magnitude of heart rate reduction observed with Metoprolol CR/XL was compared between genotypes using unpaired t-tests.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Six hundred individuals (136 from the UK, 464 from Holland) were successfully genotyped. We were unable to identify the β1AR Arg389Gly genotype in 118 individuals. These latter patients were slightly older and tended to have a higher NYHA class of heart failure.

There were no significant differences in the baseline characteristics of the three genotypes (Table 1). Of the 600 individuals successfully genotyped 156 individuals suffered an adverse event (26%) defined as all-cause death or hospitalisation. Patients in the event group as compared to the event-free group, were of significantly higher NYHA Class (P=0.001), had a significantly lower ejection fraction (P=0.003) and were more likely to have an ischaemic cardiomyopathy (P=0.046).


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  		Table 1 Baseline characteristics for each polymorphism

 
The overall prevalence of the three genotypes in the entire cohort was ArgArg (homozygous wild-type) 51.3%, ArgGly (heterozygote) 40.2%, GlyGly (homozygous mutant) 8.5% (Table 2). The genotype frequencies were in Hardy–Weinberg equilibrium (P=0.69). The allelic prevalence, arginine 0.72 glycine 0.28, was consistent with previous population studies [11,13,14].


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  		Table 2 Genotype prevalence in event group and event-free group and genotypic RRs

 
There was no significant difference in distribution of alleles/genotypes between the event group and non-event group (Table 2). Using ArgArg genotype as the reference, the RR for the ArgGly genotype was 0.92; CI, 0.66–1.29; and for the GlyGly genotype it was 1.05; CI, 0.60–1.85; P=0.86 (Table 2). Grouping together the ArgGly heterozygous patients with the GlyGly mutant homozygous patients and comparing these collectively with the ArgArg wildtype homozygous patients, again no significant benefit of the presence of the Gly allele was observed, RR=0.94; CI, 0.69–1.29; P=0.72 (Fig. 3a). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed for both the 600 patients studied (RR=0.60; CI, 0.44–0.83; P=0.002; Fig. 3b) and also for the entire cohort of 718 patients (RR=0.66; 95% CI, 0.50–0.87; P=0.003). Equally, no benefit of the Gly389 allele was observed in the Metoprolol CR/XL subgroup, RR=0.93; CI, 0.62–1.40; P=0.74 and placebo subgroup, RR=1.0; CI, 0.61–1.64; P=0.99. These results therefore, provide no support to the theoretical association of this polymorphism with adverse events.


Figure 3
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  		Fig. 3 Kaplan–Meier event-free survival curves: Panel A: ArgArg vs. (ArgGly and GlyGly) RR=0.94; CI, 0.69–1.29 P=0.72. Panel B: Placebo vs. Metoprolol CR/XL RR=0.60; CI, 0.44–0.83 P=0.002.

 
No association of this polymorphism was found with the baseline haemodynamic variables of resting heart rate, systolic and diastolic blood pressure (Table 1). Furthermore, the dose of Metoprolol CR/XL prescribed and the heart rate reduction attained at each clinic visit was not significantly different between genotypes (P>0.1 at each visit).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Based on a mean follow-up of approximately 12 months (range: 7–17 months), we have observed that the distribution of genotypes of the Arg389Gly polymorphism was identical in individuals who either had an event (death or hospitalisation) or were free from an event. Furthermore, the distribution of genotypes as a whole was the same as has been previously reported for populations not selected on the basis of a potential cardiovascular risk [11,13]. No significant effect on event-free survival of the Gly389 allele was observed. There appears therefore, to be no association of this polymorphism with either heart failure itself, or its outcome. Our inability to study all 718 patients randomised into the MERIT study in the UK and Netherlands, might conceivably have affected our observations as a result of a genotype-induced selection bias. However, for this to be true, the genotype prevalence in the 118 patients not studied, would need to have been dramatically different to that observed for the 600 patients studied. This seems most unlikely as the observed prevalence in the included patients exhibits evidence of being in Hardy–Weinberg equilibrium and is also identical to the allele distribution reported in a range of other publications [11,13–17]. Individuals provided blood samples approximately 3 months following randomisation (mean±S.D.: 88±17 days). Repeating the analysis, using this venesection date as day zero and thereby excluding all events prior to blood sampling, again no significant effect on event-free survival of the Gly389 allele was observed (RR=0.88; CI, 0.62–1.25; P=0.485). However, as in the original analysis, a similar beneficial effect of beta blockade was seen (RR=0.62; CI, 0.44–0.89; P=0.008).

Given the in vitro functional effect of the Arg389Gly we sought an association with baseline heart rate and blood pressure. We found no evidence of an intermediate effect manifested as either heart rate or blood pressure differences related to genotype. However, this haemodynamic analysis should be regarded with some caution. Individuals had variable ejection fractions and were on other therapeutic agents both of which would influence baseline haemodynamics. Interestingly, the absence of a physiological effect in vivo is further supported by data from three recent small studies and also earlier research carried out by our group [14–17].

We also sought a potential interaction between Metoprolol CR/XL and this functional polymorphism. Three hundred and seven patients within this sub-study cohort received Metoprolol CR/XL and a mean heart rate reduction of 16 bpm (S.D. 11.55) was observed similar to that seen in the MERIT-HF study as a whole. However, no influence of this functional polymorphism was identified on the magnitude of this in vivo pharmacological effect. This supports data from a recent retrospective study of hypertensive patients in whom this polymorphism did not influence the haemodynamic response to beta-1 selective blockade [15]. Moreover, in our survival analysis, the presence of the Gly allele did not influence the clinical benefit conferred by Metoprolol CR/XL (data not shown).

The marked difference in biochemical function in vitro of this important receptor polymorphism provides rationale for a potential influence on morbidity/mortality in heart failure. Therefore, our observation that such a difference does not translate to a measurable effect in man is of particular interest. However, it should be emphasised that the evidence for functional differences was derived from a recombinant system using cultured hamster fibroblasts [11]. Furthermore, recent experimental work suggests that Arg389 receptors desensitise more readily than the Gly389 variant, thus potentially offsetting differences in vivo [18]. Finally, cAMP levels in the cell are dependent on many processes, particularly breakdown by phosphodiesterase activity.

In a complex pathogenic process like heart failure, the interaction of multiple polymorphic loci is more likely to determine phenotype than a single polymorphism in isolation. In addition to the β1AR, the sympathetic nervous system embraces other adrenergic receptors, which modulate myocyte apoptosis, hypertrophy, fibroblast and vascular smooth muscle cell proliferation, inflammation and platelet aggregation [19–23]. These too, display polymorphisms [24,25]. The Ser49Gly polymorphism located within the amino terminal of the β1AR itself may play a part by modifying β1 receptor expression [13,26]. Furthermore, potential variants of the numerous proteins downstream of the β1AR need to be considered.

Our observations support those identified by Tesson et al. who identified no association of the Arg389Gly polymorphism and outcome in idiopathic dilated cardiomyopathy [27]. However, a small study carried out by Wagoner et al. focused on prognostic cardiopulmonary exercise parameters in heart failure patients and identified significantly lower peak oxygen consumption in those possessing the Gly allele [28]. Data from a recent association study suggest that the other variant of the β1AR (Gly49) is associated with improvement in long-term survival in patients with heart failure [29]. Yet, following correction for other relevant variables, the survival difference was of borderline significance.

By grouping together the GlyArg heterozygotes with the GlyGly homozygotes and comparing them collectively (n=292) with the ArgArg genotype (n=308), we were able to increase the power of the study, and a RR for the Gly allele of 0.94 suggests that it has no significant effect on the incidence of adverse events in heart failure. However, it is noteworthy that the lower confidence limit measuring 0.69 approaches that of the beta-blocker effect (RR=0.60) so a small beneficial effect is still possible, although it is much less likely that we have missed a general effect of major clinical significance.

In conclusion, 600 individuals were followed for a mean of 12 months in order to observe 156 events. We could not detect any appreciable effect of the Arg389Gly polymorphism on clinical outcome parameters (all-cause death or hospitalisation) or on baseline physiological parameters. However, in this same sub-study cohort we were able to confirm a significant beneficial effect of beta blockade. Consequently, we consider that we have ruled out a modulating effect for the β1AR 389 variant, at least to the extent observed with beta antagonists. Furthermore there was no evidence for a pharmacogenetic effect with this common polymorphism.


   Acknowledgements
 
Professor John Wikstrand for his help in the preparation of this MERIT-HF Substudy and the other members of the MERIT-HF Study Group. (For names of members and their affiliations see Ref. [8].) This project was funded by: Fellowship Grant from the British Heart Foundation, Netherlands Heart Foundation, Astra Zeneca, The Netherlands.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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G. W. Dorn II and S. B. Liggett
Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure
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