Pharmacogenetics of the Human Beta-Adrenergic Receptors

Pharmacogenetics of the human beta-adrenergic receptors

MRG Taylor The beta-adrenergic receptors (ADRBs) are cell surface receptors that play central roles in the sympathetic nervous system. Pharmacological targeting Adult Medical Genetics Program, University of of two of these receptors, ADRB1 and ADRB2, represents a widely used Colorado at Denver and Health Sciences, Aurora, therapeutic approach for common and important diseases including asthma, CO, USA hypertension and heart failure. Genetic variation in both ADRB1 and ADRB2 has been linked to both in vitro and clinical disease phenotypes. More Correspondence: Dr MRG Taylor, Adult Medical Genetics recently, interest has shifted to studies that explore potential interaction Program, University of Colorado at Denver and between variation in ADRBs and medications directed at these important Health Sciences, 12635 East Montview Blvd, receptors. This paper reviews the current state of knowledge and under- Suite 100, Aurora, CO 80045, USA. standing of ADRB genetic variation and explores the likely direction of future E-mail: [email protected] studies in this area. The Pharmacogenomics Journal (2007) 7, 29–37. doi:10.1038/sj.tpj.6500393; published online 25 April 2006

Keywords: pharmacogenetics; beta adrenergic receptors; asthma; cardiovascular disease; genetics; haplotype

Introduction

The autonomic nervous system is responsible for regulating the physiological demands of vascular and visceral smooth muscle as well as exocrine and endocrine glands. Through a series of counterbalancing mechanisms, autonomic homeostasis is continually sought as the organism responds to changes in its environment. Endogenous proteins bind to cell surface receptors and transmit signals through the divisions of the autonomic nervous system and coordinate parasympathetic and sympathetic responses to maintain relative constancy of the internal environment of the organism. In the sympathetic nervous system, the adrenergic receptors (both alpha and beta subclasses) are of central importance in mediating the response of cells and organs to sympathetic discharges. In this review, the beta-adrenergic receptors (ADRBs) are discussed in the context of naturally occurring genetic variation in the ADRB genes. Although ADRBs mediate many sympathetic responses, cardiovascular and asthma phenotypes, which have been most thoroughly investigated to date, are primarily discussed here. The described pharmacogenetic studies and the potential relevance of ADRB polymorphisms on clinical phenotypes in humans are highlighted. Beta-adrenergic receptors are important drug targets for asthma and cardiovascular conditions including hypertension and congestive heart failure. Inhaled beta-receptor agonists (e.g. albuterol) and antagonists (e.g. ‘beta-blockers’) Received 21 February 2006; accepted 24 February 2006; published online 25 April remain among the mostly commonly prescribed medications in adults to treat 2006 asthma and cardiovascular disease, respectively. It has long been accepted that Pharmacogenetics of the human ADRBs MRG Taylor 30

abnormal airway function plays a role in the pathogenesis of ADRB1 and ADRB2 are intronless genes encoding 477- and asthma, and genes, including the ADRBs, are strongly 413-amino-acid proteins, respectively; ADRB3 contains at implicated in susceptibility and treatment response to least one intron15–17 needed for the 408 amino-acid protein. asthma.1–4 Genetics are also important in the cardiovascular In spite of moderate differences in amino-acid sequences, system, which has the tasks of delivering oxygen and the three ADRBs share a common structure with an nutrients to tissues and organs and must also provide a extracellular amino terminus, seven transmembrane span- mechanism for the transport and removal of metabolic ning domains and a cytoplasmic carboxy terminus (Figure by-products for elimination by the body. The cardiovascular 1).18 Binding of agonist to the receptor leads to a guanine system has evolved to function under a wide range of nucleotide binding protein (Gs protein) coupled response physiologic demands and can rapidly adapt to the changing and conversion of adenosine 50 triphosphate to cyclic needs of the host. Beta-adrenergic receptors play an adenosine 30,50 monophosphate (cAMP) by adenylate cy- important role in the extrinsic control of cardiac contrac- clase.5,19 Intracellular rises in cAMP provide an indirect tility and function. measure of ADRB activity. Increased cAMP stimulates a Beta-adrenergic receptors are G-protein-coupled receptors chain of events that culminates with removal of calcium located on the surface of effector cells. They bind both from contractile protein (faster relaxation in the case of epinephrine and norepinephrine as well as exogenously myocytes) and increased activation of contraction through administered drugs, including beta-agonists and antagonists greater calcium cycling; the global effect is improved systolic 5 (‘beta-blockers’). For the cardiovascular system, ADRBs and diastolic function. Stimulation of Gs also directly mediate alterations in myocardial metabolism, heart rate activates effectors, such as the L-type calcium channel.6 The and systolic and diastolic function.5,6 In general, agonist importance of the ADRB system in cardiovascular physiol- binding increases cardiac contractile strength, relaxation ogy has been explored on multiple levels and led to the and heart rate with acute changes observed within seconds discovery of multiple polymorphic variants in this system of agonist release. Indeed, the prompt responses mediated (Figure 1).14,20–39 through activation of ADRBs are critical to regulation of circulatory homeostasis and to the survival of the organism ADRB1 polymorphisms (e.g. providing an ability to maintain adequate blood Twenty-three polymorphisms of ADRB1 have been described pressure in the face of acute blood loss). Although the and 13 of these predict amino-acid changes in the ADRB1 presence of a rapidly responding adrenergic system is critical protein.14,40 As ADRB1 does not have a recognized role in to survival, prolonged activation of these pathways has the pathogenesis of asthma, the majority of genetic associa- deleterious consequences. Chronic stimulation of adrener- tion studies have focused on cardiovascular phenotypes. gic pathways is harmful and inhibits myocyte growth and Several of the polymorphisms are quite rare and have not function.6 Persistent stimulation of ADRBs leads to down- been widely studied. The Arg389Gly was the first ADRB1 regulation of ADRB signaling by decreasing receptor sensi- missense polymorphism reported with the polymorphism tivity to catecholamines and by increasing inhibitory G localizing to the intracellular cytosplasmic tail of ADRB1 7 41 protein (Gi) activity. In chronic heart failure for instance, and showing a minor allele (Gly) frequency of 0.26. Mason catecholamines are elevated, leading to tonic adrenergic et al.41 have proposed that this tail domain interacts with signaling; this increased level of cardiac adrenergic drive is the Gs protein and influences signal transduction. The NCBI an important prognostic indicator in heart failure.8 database reports that a valine residue (rs17875445) may also be found at the 389 position, accounting for approximately 3% of the alleles, but this variant has not been studied The three beta-adrenergic receptor subtypes extensively. Other known ADRB1 missense polymorphisms There are three subtypes of ADRBs (ADRB1, ADRB2 and are Ser49Gly, Ala59Ser, Arg318Ser, Lys324Arg, Ala343Thr, ADRB3) encoded by three separate genes. ADRB1 and Glu352Asp, Arg399Cys, Arg400Leu, His402Arg, Thr404Ala, ADRB2 have been well studied and have important effects Pro418Ala and Asp460Glu.14,42,43 The Ser49Gly and Ala59- on pulmonary and cardiac physiology. In the heart, ADRB1s Ser polymorphisms are located in the extracellular amino are the predominant subtype expressed and mediate terminus and are thought to affect ligand binding. Variants increases in inotropy and chronotropy when stimulated.5 in the intracellular carboxy terminus (Arg389Gly, ADRB2s are abundantly expressed in bronchial smooth Arg399Cys, Arg400Leu, His402Arg, Thr404Ala, Pro418Ala, muscle and activation of them results in bronchodilation, Asp460Glu) could modulate Gs protein coupling as is a fact exploited in the use of inhaled beta-agonist medica- hypothesized for the Arg389Gly variant. The Ser49Gly tions for asthma. ADRB2s are also expressed on cardiac polymorphism is in linkage disequilibrium with the 389 myocytes (inotropy) and vascular smooth muscle cells locus.18 (vasodilation). ADRB3 has been least studied to date. Recent data suggest that the ADRB3 subtype might mediate ADRB2 polymorphisms cardiovascular effects to a modest degree and may even act There are 12 polymorphisms reported for the ADRB2 coding to weaken cardiac contractility.9–13 ADRB3 is not consis- region (Figure 1).14,35,43 Five of these polymorphisms predict tently expressed in the human heart and the importance of changes to the amino-acid sequence: Gly16Arg, Gln27Glu, its role on cardiovascular disease is not known.14 Val34Met, Thr164Ile and Ser220Cys. A polymorphism in the

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Figure 1 Location of reported ADRB1 and ADRB2 polymorphisms. The location of the reported (literature and in National Center of Biotechnology Information database) polymorphisms is shown for the ADRB1 and ADRB2 genes and the ADRB2 leader peptide sequence. Amino-acid positions are numbered and the wild-type and polymorphic variant are indicated. Red diamonds indicate sites of missense polymorphisms that alter the amino- acid sequence of the protein. Yellow squares indicate polymorphisms of the DNA sequence that do not translate into an alteration of the amino-acid residue (silent polymorphisms). untranslated portions of the gene has also been described inhibition by beta-blockers, but the overall significance of and may be of biological relevance.44 The separate cardiac ADRB3s remains uncertain.50,51 19-amino-acid ADRB2 regulatory peptide is encoded in the Genetic polymorphisms are present in ADRB3s and the 50 upstream region of ADRB2. The last residue of this Trp64Arg was the first one to be studied in obesity, diabetes oligopeptide is polymorphic (Cys-19Arg). Accounting for and hypertension.9,12,39,52,53 In a Pima Indian population, these 13 polymorphisms of ADRB2 gene region, one would the Arg64 (minor) allele appeared to be a risk factor for predict a potential for 8192 (213) haplotypes from the earlier onset of diabetes.54 Later studies have reported theoretical combinations of each variant at each loci. Not inconsistent results with respect to the Trp64Arg variant surprisingly, there is linkage disequilibrium present and the and diabetic and obesity phenotypes.55–57 More recently, the number of haplotypes encountered in humans is much Trp64Arg polymorphism was suggested to interact with lower. In one study, all 13 ADRB2 polymorphisms were obesity in conferring risk of pre-eclampsia with the rarer genotyped in 121 Caucasian asthmatics and 77 controls Arg64 variant being possibly protective against pre-eclamp- (396 chromosomes), which resulted in 12 inferred haplo- sia in overweight women.47 As the pharmacogenetic data on types; five of these haplotypes appeared to represent 95% of ADRB3 polymorphisms are less developed than those for the total haplotype pool.44 Althouth the population size in ADRB1 and ADRB2, the remainder of this review will this study was modest, ethnic differences in haplotype concentrate on the latter two receptors. frequency were observed, which may impact the general- izability of future pharmacogenetic studies. Functional studies of ARDB1 polymorphisms Two ADRB1 polymorphisms (Ser49Gly and Arg389Gly) have been widely studied owing to studies supporting both ADRB3 polymorphisms functional effects on ADRB1 activity and on phenotypes in ADRB3s are principally localized to adipose tissue, but are human studies. The Gly49 allele (as compared to Ser49) also expressed in pancreas, colon, prostate, skeletal muscle showed altered glycosylation and a more pronounced and cardiac atrial tissues.45,46 The adipose tissue expression agonist-induced receptor downregulation in a hamster has generated interest in whether ADRB3s are important in fibroblast model.58,59 This might translate into resistance modifying obesity phenotypes. ADRB3 agonists in rodents to chronic beta-adrenergic stimulation through disease or show an increase in lipolysis and energy expenditure and medication. The Arg389 alleles manifest increased function mice lacking ADRB3s develop obesity.47,48 Human cardiac in vitro as compared to Gly389 receptors showing higher tissue and blood vessels contain ADRB3s and upregulation basal levels of adenylyl cyclase activity and heightened of ADRB3s in failing hearts has been demonstrated.49 ADRB3 sensitivity to stimulation by isoproterenol. Thus, the Arg389 may be clinically important in the cardiovascular system as may have inherently superior coupling to Gs (stimulatory G there is evidence for activation by beta-agonists and protein) and increased signal transduction, which is fitting

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with some of the observed population based studies in Interaction of ADRB1 Arg389Gly and alpha-2-C adrenergic humans.41 polymorphism The ADRB1 Arg389Gly polymorphism appears to interact Functional studies of ADRB2 polymorphisms with another polymorphism in the alpha-2-C adrenergic The Arg16Gly and Gln27Glu polymorphisms show altered receptor (ADRA2C). A functional 4-amino-acid deletion of downregulation of ADRB2 in a Chinese hamster fibroblasts the ADRA2C (del322–325) modulates presynaptic release of system.60 In healthy subjects, the Arg16 variant has norepinephrine. In a case–control study of heart failure (189 enhanced isoproterenol-mediated desensitization of the affected; 159 controls), del322–325 homozygotes, who vasculature and enhanced isoproterenol induced-venodila- tonically release more norepinephrine, had an increased tion.61 The Ile164 variant has increased binding affinity for odds ratio of 5.65 (95% CI 2.57–11.95) of heart failure. norepinephrine, epinephrine and isoproterenol. The expla- When the Arg389 homozygotes, who experience enhanced nation for this is not immediately clear as the 164 position is ADRB1 signaling, were added into this model, the odds of localized to the fourth transmembrane domain and is heart failure was increased to 10.11 (95% CI 2.11–44.53) for unlikely to come into direct contact with ligand.62 Trans- carriers of both rare variants. These data were only true in Black subjects, as the number of double homozygotes in genic mice overexpressing Ile164 have lower resting heart 27 rates and lower levels of adenylyl cyclase than mice Caucasians was too small for analysis. expressing the Thr164 variant.63 One function of the ADRB2 leader peptide is to modulate ADRB2 expression, and this is influenced by the Cys-19Arg polymorphism.64,65 ADRB2 association studies

Polymorphisms in ADRB2 have been more extensively ADRB1 association studies studied because the potential phenotypes of interest extend beyond cardiovascular traits to asthma, obesity and dia- Polymorphisms in ADRB1 have been evaluated against a betes. Although environmental triggers are believed to be number of phenotypes, mostly related to the cardiovascular necessary for the development of asthma, a major focus of system. The most widely studied variants have been the current research is on the genetic factors, including ADRB2s, Ser49Gly and Arg389Gly polymorphisms. In a collection of which interact with environmental exposures.1,71 A recent Asian patients, Ser49 homozygotes had higher mean heart meta-analysis concluded that the Gly16 allele predisposes to rates than Gly49 homozygotes.66 Later studies did not nocturnal asthma and asthma severity.72 Another study reproduce this finding in different ethnic populations24,67 reported reduced forced expiratory volume and a greater although one study did report a trend towards a more decline in lung function in cystic fibrosis patients carrying pronounced lowering of mean heart rate after antihyperten- the Gly16 allele.30 Gly16 has also been linked to differential sive therapy in Gly49 homozygotes with baseline hyperten- response to beta-agonist therapy (albuterol) in asth- sion and left ventricular hypertropy.68 The Arg389 variant matics.73,74 was associated with elevated diastolic blood pressure and In hypertensive populations, ADRB2 genetic association higher resting heart rate in a study that used both a case– studies have yielded mixed results. Hypertension has been control and a sib pair analysis design.24 The external validity associated with the Arg16 and Gly16 alleles in different of these findings was strengthened by similar conclusions studies.23,75 These contradictory findings could be explained being made with the Arg389 variant in a different study by differences in the populations. A subsequent combined population.67 analysis of over 1800 hypertensive cases and controls found ADRB1 polymorphisms have been studied in the context no association with the hypertensive phenotype at the of heart failure, where beta-blocking medications are widely Arg16Gly locus.31 In an analysis of siblings highly dis- used therapeutic agents. The Ser49Gly polymorphism does cordant for blood pressure (427 subjects from 55 families), not appear to be an independent risk factor for heart failure the Gly16 was associated with elevated resting blood in case–control studies.22,25,69 One study did report Gly49 as pressure. This work was extended to nearly 1300 subjects a risk factor for idiopathic dilated cardiomyopathy, but the and the association findings remained significant.76 The modest population size studied (37 cases and 40 controls) investigators then added 291 additional families from a and difference in allele frequency as compared to other differing geographic region and the Gly16 allele no longer studies limit a firm conclusion that Gly49 carriers are at associated with elevated blood pressure; interestingly, the elevated risk.21,42 This polymorphism, however, may have a Gln27 allele was found to be predictive of systolic and mean role in progression of heart failure as the Ser49 variant was arterial blood pressure in the final population (odds ratio associated with a reduced 5-year survival (risk ratio 2.34; 1.80; P ¼ 0.023). P ¼ 0.003). The other major ADRB1 polymorphism, Arg389- In healthy individuals, ADRB1s are far more abundant Gly, is not a clear risk factor for heart failure. In a study of than ADRB2s in the human heart; this situation changes in 224 patients with heart failure treated with the beta-blocker heart failure where the proportion of ADRB2s is increased to carvedilol, Arg389 homozygotes experienced a greater approximately 40%.77–79 These data could be interpreted to improvement in the ejection fraction (8.7 vs 0.93%; mean that ADRB2 polymorphisms might have greater effects Po0.05) as compared to Gly389 homozgyotes.70 in heart failure.14 In a study of 259 heart failure patients, the

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Ile164 variant was predictive of a combined end point of influence the differential expression of clinically important death or cardiac transplantation (relative risk 4.81; phenotypes. The enthusiasm for these data are tempered by Po0.001). The Arg16Gly and Gln27Glu loci were also problems generally common to genetic association studies: studied and did not yield significant findings.37 In another limited sample sizes, suboptimal matching of cases and heart failure study, the Ile164, Gly16 and the combination controls, subgroup analyses and focuses on secondary of Gly16 and Gln27 variants predicted lower cardiopulmo- outcomes, lack of corrections for multiple comparisons nary exercise capacity.80 More recently, the Arg16 allele has and few successful attempts to replicate results in indepen- been linked to higher heart rate and elevated cardiac dent populations.83,84 Some have suggested that haplotype adrenergic drive (measured by norepinephrine spillover) approaches may address some of these problems and the and the Gln27 allele predicted a more favorable response to density of haplotype data generated by the HapMap project carvedilol in heart failure subjects.81,82 (http://www.hapmap.org/) makes these types of studies Thus, polymorphisms in ADRB1 and ADRB2 have support increasingly feasible.84 Currently, only a few haplotype- for biological relevance in both in vitro and clinical studies. based ADRB studies have been published and their focus has Not all results have been consistent, however, and few largely been on those ADRB polymorphisms that have been studies have successfully replicated findings in larger previously reported to associate with clinical phenotypes populations. In most clinical studies, surrogate markers of (Figure 2). By transfecting ADRB1 genes with different clinically important end points have been studied and the combinations of the Ser49Gly and Arg389Gly polymorph- importance of variation at these polymorphisms on major isms, Sandilands et al.85 noted differences in the production indicators of morbidity and mortality is still not understood. of cAMP after isoprenaline stimulation. In a study of Furthermore, the utilization of ADRB polymorphic data in 862 subjects undergoing bicycle exercise training, ADRB1 the clinical care of patients affected with cardiovascular or Haplotype 1 (Figure 2) predicted greater aerobic power pulmonary diseases remains largely theoretical. (measured by peak oxygen uptake) as compared to Haplo- type 2 or 3.86 Haplotype approaches to ADRB1 and ADRB2 Four polymorphisms have been included in studies of The results of previous genetic association studies described ADRB2 haplotypes: Cys-19Arg, Gly16Arg, Gln27Glu and above have been intriguing and several support hypotheses Thr163Ile. In one such analysis of terbutaline-mediated that functional polymorphisms in ARDB1 and ADRB2 venodilation of the dorsal hand vein in 35 subjects,

Figure 2 Haplotypes of ADRB1 and ADRB2. The location of missense (red diamonds) and silent (yellow squares) polymorphisms is depicted for ADRB1 (a) and ADRB2 (b). Below each gene are representative haplotypes indicated by red (common allele) or white (rare allele) shading of the missense polymorphisms. Haplotypes for each gene are numbered (arbitrariliy) on the left of the figure. Haplotype frequencies (italics) as predicted for ADRB186 and ADRB290 are indicated. For ADRB2, the leader peptide Cys-19Arg polymorphism is also shown. Although four polymorphisms are depicted as contributing to the ADRB2 haplotype, the Cys-19Arg variant was not genotyped in the calculation of the ADRB2 haplotype frequencies. Astericks (*) indicate sites of 2 or more polymorphisms.

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Haplotype 1 (Figure 2) predicted greater response to terbuta- an effect that was not observed in those patients taking line than Haplotype 2 or 3 (the Cys-19Arg polymorphism higher doses.69 was not genotyped in this work).87 Oostendorp et al.88 used Two studies looked at ADRB2 genotypes in reactive airway human lymphocytes and measured desensitization to iso- disease. In a case–control study of 543 Caucasian males, proterenol-induced cAMP accumulation; ADRB2 Haplotype ADRB2 Arg16 showed a trend towards bronchial hyper- 2 showed significantly greater desensitization as compared responsiveness to methacholine (cholinergic agonist) cha- to Haplotypes 1 or 3 (the Thr164Ile polymorphism was not llenge. The effect became statistically significant when only genotyped in this work). The authors suggest that the non-smokers were considered, where Arg16/Gln27 (Figure 2, differential haplotype effect may be important for the ADRB2 Haplotype 1) subjects had greater hyper-responsive- regulation of type 2 helper cells in asthma inflammation. ness.96 In the first prospective trial to stratify treatment arms In a larger study of 642 overweight or obese subjects, ADRB2 by ARDB2 genotypes in asthma, Arg16 and Gly16 homo- Haplotype 1 predicted increased levels of triglycerides and zygotes (n ¼ 37 and 41, respectively) were enrolled and LDL-cholesterol (the Thr164Ile polymorphism was not randomized to placebo or inhaled albuterol in a crossover genotyped in this work).89 The largest ADRB2 haplotype design. In the treatment phase, albuterol-treated Gly16 study to date involved genotyping of 523 patients who had homozygotes had improvements in morning peak expira- myocardial infarction from a prospectively followed cohort tory flow rates as compared to placebo (14 l/min improve- of 14 916 initially healthy American men. Four controls ment; 95% CI 3–25; P ¼ 0.0175). The opposite was observed (n ¼ 2092) were matched for each case and Haplotype 4 and for the Arg16 homozygotes, who actually showed an average the combined group of Haplotypes 1 and 3 had significantly of 10 l/min drop in their expiratory flow rates (95% CI: À19 altered risk of myocardial infarction with odds ratios of to À2; P ¼ 0.0209). The unfavorable response to albuterol 0.178 (95% CI: 0.043–0.737; P ¼ 0.017) and 1.235 (95% CI: therapy in the Arg16 homozygotes prompted the authors to 1.031–1.480; P ¼ 0.022) respectively (the Cys-19Arg poly- suggest that caution may need to be exercised in this group morphism was not genotyped in this work).90 of subjects.73

Pharmacogenetic studies of ADRBs Accumulating evidence suggests that ADRBs are important Implications for pharmacogenomics in the pathogenesis and severity of human disease states, including cardiovascular, pulmonary and obesity disorders. The bulk of the data indicates that variation in ADRBs does That ADRBs are major targets of pharmacological therapy impact clinically relevant phenotypes. A recent shift (beta receptor agonists and antagonists) has not escaped towards studies that evaluate the response to medications notice and efforts are now underway to account for as determined by ADRB genotype adds momentum to the polymorphic variation in ADRBs to develop more rationale concept that individualized therapy for heart failure, hyper- therapeutic approaches in humans.83,91,92 For ADRB1, four tension and/or asthma may soon be realized. For ADRB1, the recent studies have reported exciting finding of interactions Gly49 and Arg389 variants seem, on balance, to be between adrenergic directed agents and cardiac phenotypes. the variants that perform more favorably in heart failure In a study of 30 healthy males, ADRB1 Arg389 homozygotes patients given beta-blockade. In the case of ADRB2, the data showed greater increases in fractional shortening upon reported by Israel et al.73 suggest an intriguing negative exposure to the non-selective beta-agonist dobutamine as effect of Arg16 alleles on short-term beta agonist therapy. compared to subjects carrying Gly389 alleles (61.9 vs 52.8; Whether this finding holds true for long-term exposure to P ¼ 0.001). This translated to a 19 mmHg difference in beta-agonist therapy remains to be clarified. Haplotypes of systolic blood pressure at the highest dobutamine dose ADRB2 may also be important in myocardial infarction risk (P ¼ 0.005).93 In 61 patients with heart failure who had not as suggested by at least one study.90 Much remains to be previously received beta-blocking therapy, the ADRB1 learned and studies that integrate haplotype data and also Arg389 homozygotes had significant improvements in account for interactions between ADRB1 and ADRB2 loci ejection fraction in response to an ADRB1 blocking agent may ultimately prove more fruitful studies of individual (metoprolol) and showed overall improvements as com- polymorphisms. The example of the interaction between pared to Gly389 carriers. Carriers of ADRB1 Gly49 had ADRB1 Arg389Gly and the ADRA2C del 322–325 poly- improved left-ventricular end-diastolic diameters.94 In a morphism highlights the importance of other genes in the related study, patients with Gly389 treated with metoprolol adrenergic pathway. required more increases in their heart failure medications in The road ahead remains a steep one for translating these a 10-week study as compared to Arg389 subjects; interest- sorts of data into clinical practice. A foundation for this ingly, the same held true for carriers of Gly49 alleles.95 journey will likely be developed from extending the studies Somewhat at odds with these findings are data from a of ADRB polymorphisms to large DNA banks, ideally where subgroup analysis of 375 idiopathic dilated cardiomyopathy prospective data have been collected. Such an effort may patients (375 cases and 492 controls) where Ser49 carriers require the partnership of several research groups, and data required higher doses of beta-blocking medications. In sharing and replication in multiple data sets is recom- patients receiving p50% of their targeted full dose of beta- mended. Convincing data from this method of approach blockade, 5-year mortality was lower in the Gly49 carriers, can then form the basis for prospective clinical trials where

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stratification by haplotype (or genotype) is performed. The 21 Podlowski S, Wenzel K, Luther HP, Muller J, Bramlage P, Baumann G shift from the current approach in trials of ‘mere’ randomi- et al. Beta1-adrenoceptor gene variations: a role in idiopathic dilated zation of clinically homogenous subjects (who are actually cardiomyopathy? JMolMed2000; 78: 87–93. 22 Borjesson M, Magnusson Y, Hjalmarson A, Andersson B. A novel genetically heterogenous) to a genetic-based paradigm will be polymorphism in the gene coding for the beta(1)-adrenergic receptor essential if the benefits of ADRB haplotype-directed thera- associated with survival in patients with heart failure. Eur Heart J 2000; pies are to be realized. 21: 1853–1858. 23 Bengtsson K, Orho-Melander M, Melander O, Lindblad U, Ranstam J, Rastam L et al. Beta(2)-adrenergic receptor gene variation and hyperten- Acknowledgments sion in subjects with type 2 diabetes. 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