Background Sustained cardiac adrenergic stimulation has beenimplicated in the development and progression of heart failure.Release of norepinephrine is controlled by negative feedbackfrom presynaptic 2-adrenergic receptors, and the targets ofthe released norepinephrine on myocytes are 1-adrenergic receptors.In transfected cells, a polymorphic 2C-adrenergic receptor (2CDel322–325)has decreased function, and a variant of the 1-adrenergic receptor(1Arg389) has increased function. We hypothesized that thiscombination of receptor variants, which results in increasedsynaptic norepinephrine release and enhanced receptor functionat the myocyte, would predispose persons to heart failure.
Methods Genotyping at these loci was performed in 159 patientswith heart failure and 189 controls. Logistic-regression methodswere used to determine the potential effect of each genotypeand the interaction between them on the risk of heart failure.
Results Among black subjects, the adjusted odds ratio for heartfailure among persons who were homozygous for 2CDel322–325as compared with those with the other 2C-adrenergic receptorgenotypes was 5.65 (95 percent confidence interval, 2.67 to11.95; P<0.001). There was no increase in risk with 1Arg389alone. However, there was a marked increase in the risk of heartfailure among persons who were homozygous for both variants(adjusted odds ratio, 10.11; 95 percent confidence interval,2.11 to 48.53; P=0.004). The patients with heart failure didnot differ from the controls in the frequencies of nine shorttandem-repeat alleles. Among white subjects, there were toofew who were homozygous for both polymorphisms to allow an adequateassessment of risk.
Conclusions The 2CDel322–325 and 1Arg389 receptors actsynergistically to increase the risk of heart failure in blacks.Genotyping at these two loci may be a useful approach for identificationof persons at risk for heart failure or its progression, whomay be candidates for early preventive measures.
Idiopathic dilated cardiomyopathy and ischemic cardiomyopathyare the major causes of congestive heart failure in the UnitedStates. The pathogenesis of the former is unknown; the latteris caused by ischemia or infarction from coronary artery disease.Regardless of the initial insult, studies suggest that sustainedsympathetic drive, which is a consequence of depressed cardiacoutput, plays a part in the progression of heart failure.1,2,3However, there is substantial variation among persons in theexpression and function of adrenergic receptors, the developmentand progression of heart failure, and the response to beta-blockertherapy.4,5,6,7
We undertook a study to determine whether functional polymorphismsof selected adrenergic receptors may be important factors insuch variation. The basis of our hypothesis is summarized inFigure 1. Prejunctional 2-adrenergic receptors (the 2A and 2Csubtypes) regulate the release of norepinephrine from cardiacsympathetic nerves.8,9 A common coding polymorphism of the genefor the 2C-adrenergic receptor — the deletion of fourconsecutive amino acids (Del322–325) — results ina substantial loss of agonist-mediated receptor function intransfected cells.10 A loss of normal synaptic autoinhibitoryfeedback caused by this dysfunction would result in enhancedpresynaptic release of norepinephrine.9,11,12 We therefore hypothesizedthat persons with this 2C-adrenergic–receptor variantwould be at increased risk for heart failure.
Figure 1. Basis of the Hypothesis That the 2CDel322–325 and 1Arg389 Receptors Act Synergistically as Risk Factors for Heart Failure.
The 2C-adrenergic receptor (along with the 2A-adrenergic receptor) inhibits norepinephrine release at cardiac presynaptic nerve endings through negative feedback. The presence of the dysfunctional 2CDel322–325 receptor would be expected to result in enhanced norepinephrine release. The 1-adrenergic receptor is the receptor for norepinephrine on the cardiomyocyte, and the presence of the hyperfunctional 1Arg389 receptor would be expected to increase contractile response at the myocyte. The combination of increased norepinephrine release and increased responsiveness of the receptor was hypothesized to be a risk factor for heart failure.
Norepinephrine released from cardiac sympathetic nerves activatesmyocyte 1-adrenergic receptors, which couple to the stimulatoryG protein Gs, activating adenylyl cyclase and increasing intracellularcyclic AMP (cAMP). Through the subsequent phosphorylation ofseveral intracellular proteins by means of the cAMP-dependentprotein kinase A, such activation of 1-adrenergic receptorsculminates in an increase in cardiac inotropy, lusitropy, andchronotropy. Two common polymorphisms of 1-adrenergic receptorsin the human population lead to either a glycine (1Gly389) oran arginine (1Arg389) at amino acid position 389 within a Gs-couplingdomain.13 In a recombinant cell-based expression system, 1Arg389has a much greater ability to couple to adenylyl cyclase thandoes 1Gly389.13 We thus considered the possibility that 1Arg389might also predispose persons to heart failure. We hypothesizedthat persons with both the 2CDel322–325 and the 1Arg389variants would have the greatest risk of heart failure, sincenorepinephrine release and 1-adrenergic–receptor activitywould be simultaneously enhanced. To investigate whether thesevariants alone or in combination represent risk factors forthe development of heart failure, we genotyped these loci in348 subjects: 159 patients with well-characterized heart failureand 189 controls.
Methods
Study Subjects
The protocol was approved by the institutional review boardof the University of Cincinnati, and subjects provided writteninformed consent. Both control subjects and patients with heartfailure were from the greater Cincinnati area. Patients wererecruited from the University of Cincinnati Heart Failure Programbetween January 2, 1999, and January 2, 2001, through the enrollmentof consecutive eligible patients who agreed to participate inthe genetic study. Approximately 50 percent of patients in theHeart Failure Program are referred by community cardiologists,approximately 40 percent are referred by physicians within thistertiary-care center, and approximately 10 percent are self-referred.The criteria for enrollment were an age of 20 to 79 years, aleft ventricular ejection fraction of less than 35 percent,heart failure of New York Heart Association class II, III, orIV, and a diagnosis of either idiopathic dilated cardiomyopathyor ischemic cardiomyopathy. Patients with nonischemic dilatedcardiomyopathy who had antecedent hypertension were characterizedas having idiopathic dilated cardiomyopathy. Patients whoseheart failure was due to primary valvular disease, myocarditis,or obstructive or hypertrophic cardiomyopathies were not eligible.The control group consisted of persons who were unrelated toone another and were apparently healthy (as assessed by questionnaire);controls were recruited before voluntary blood donation andby newspaper advertisements. Specifically, none of the controlshad a history or symptoms of cardiovascular disease or had beentaking any medications for long periods. The racial classificationof the participants was self-reported.
Genotyping
Genomic DNA was extracted from samples of peripheral blood,and the adrenergic-receptor polymorphisms were detected as previouslydescribed.14 The adrenergic-receptor genotypes are referredto as wild-type 2C-adrenergic receptor (the more common variantwithout the deletion), 2CDel322–325 (the variant withthe deletion of four amino acids), 1Arg389, and 1Gly389. Totest for population stratification within the two racial groups,15the frequencies of alleles at nine highly polymorphic shorttandem-repeat loci16 were determined by multiplexed polymerasechain reactions with detection by multicolor fluorescence (ABIPrism 377 Sequencer, Applied Biosystems).
Statistical Analysis
Allele frequencies were computed by standard gene-counting methods.Chi-square tests of independence within each racial group wereused to test for associations between heart failure and genotypeor allele. In order to test for interactions between the 2C-adrenergic–receptorand 1-adrenergic–receptor polymorphisms, we used logistic-regressionmethods17 to model the effect of each genotype and their interactionon the risk of heart failure. Likelihood-ratio tests were usedto assess the influence of each locus and the interaction betweenthem both before and after adjustment for the potential confoundingeffects of age and sex. Finally, we used chi-square tests ofindependence to perform an analysis involving only the patientswith heart failure in order to test for associations of single-locusgenotype and two-locus genotype with hypertension status anddiagnostic group (idiopathic or ischemic). Chi-square testswere used to compare the patients with heart failure with thecontrols within each racial group in terms of the frequenciesof the short tandem-repeat alleles. When appropriate, resultsare reported as means ±SD. Kaplan–Meier plots andlog-rank tests were used to assess whether survival differedsignificantly among subgroups defined according to genotype.
Results
Characteristics of the Subjects
The characteristics of the patients with heart failure are shownin Table 1. There were 78 black patients with heart failure(mean age, 49±12 years) and 84 black controls (mean age,53±16 years). There were 81 white patients with heartfailure (mean age, 55±11 years) and 105 white controls(mean age, 36±12 years). As we have previously noted,10,18there are significant differences between blacks and whitesin the allele frequencies of both receptor variants. In thecurrent study, the 2CDel322–325 variant was more than10 times as common among black controls as among white controls(allele frequency, 0.411 vs. 0.038; P<0.001). The 1Arg389variant was somewhat less common among black controls than amongwhite controls (frequency, 0.560 vs. 0.762; P<0.001). Theseracial differences in the frequencies of the two polymorphisms,particularly the difference in the frequency of 2CDel322–325,prompted us to perform separate risk analyses for the two racialgroups.
Table 1. Characteristics of the Patients with Heart Failure.
Association between Polymorphisms and Heart Failure
Given the biologic properties of the polymorphic receptors,the primary hypothesis of the study was that 2CDel322–325,1Arg389, and particularly, the combination of the two influencethe risk of heart failure. In black persons, among whom bothvariants are relatively common, single-locus analysis (Table 2)revealed that 2CDel322–325 was more common among patientswith heart failure (allele frequency, 0.615) than among controls(allele frequency, 0.411; P<0.001). When all three possiblegenotypes were analyzed together, the association with heartfailure remained significant (Table 2). Indeed, 52.6 percentof the black patients with heart failure were homozygous forthe 2C polymorphism as compared with only 16.6 percent of theblack controls. The unadjusted odds ratio for heart failureamong subjects who were homozygous for 2CDel322–325 ascompared with subjects who were not was 5.54 (95 percent confidenceinterval, 2.68 to 11.45; P<0.001). There was no evidenceof significant confounding by age or sex, and the sex- and age-adjustedodds ratio for heart failure among subjects who were homozygousfor 2CDel322–325 was 5.65 (95 percent confidence interval,2.67 to 11.95; P<0.001). There was no evidence of a statisticallysignificant difference between black patients with heart failureand black controls in the frequency of the 1Arg389 allele (Table 2).
Table 2. Distribution of 2C-Adrenergic–Receptor Variants and 1-Adrenergic–Receptor Variants among Controls and Patients with Heart Failure.
A two-locus analysis indicated a significant interaction betweenthe 2CDel322–325 and 1Arg389 genotypes in black patientswith heart failure. The combination of the two genotypes hada multiplicative association (i.e., more than an additive effect)with the risk of heart failure (P=0.05 by the likelihood-ratiotest for interaction). Subjects were divided into four subgroupsas follows: those who were homozygous for both 2CDel322–325and 1Arg389; those who were homozygous for 2CDel322–325only; those who were homozygous for 1Arg389 only; and thosewho were not homozygous for either variant (the reference group).Among black subjects, homozygosity for 2CDel322–325 and1Arg389 was associated with a substantially increased risk ofheart failure relative to the reference group (unadjusted oddsratio, 12.67; 95 percent confidence interval, 2.70 to 59.42;P=0.001) (Table 3). When age and sex were controlled for inthe model, the odds ratio was reduced slightly but remainedsignificant (adjusted odds ratio, 10.11; 95 percent confidenceinterval, 2.11 to 48.53; P=0.004). To assess whether these findingscould be explained by differences in the frequency of this two-locusgenotype according to diagnostic group (idiopathic dilated cardiomyopathyvs. ischemic cardiomyopathy) or according to the hypertensionstatus of patients with heart failure, we performed an analysisinvolving only the patients with heart failure. Among the blackpatients, there were no differences in the frequency of thedual-polymorphism genotype between the two subgroups definedaccording to diagnosis (chi-square=1.38, P=0.71) or betweenpatients with hypertension and those without hypertension (chi-square=0.34,P=0.95).
Table 3. Genotype and Gene–Gene Interactions of 2- and 1-Adrenergic–Receptor Variants in Relation to Heart Failure.
Among white subjects, the frequency of the 2CDel322–325allele was higher among patients with heart failure than amongcontrols (0.105 vs. 0.038, P=0.01) (Table 2). Analysis in whichall three possible genotypes were considered did not show astatistically significant association with heart failure, andthe unadjusted odds ratio for heart failure among white subjectswho were homozygous for 2CDel322–325 relative to thosewho were not was 4.12 (95 percent confidence interval, 0.89to 20.98; P=0.08). The sex- and age-adjusted odds ratio was3.94 (95 percent confidence interval, 0.50 to 30.05; P=0.13).Although these odds ratios are not statistically significant,they are similar in magnitude and of the same direction as theestimate for blacks of 5.65. The lack of statistical significancein the analysis of white subjects may be due to the small numberof white subjects who were homozygous for 2CDel322–325(two controls and six patients with heart failure). As was thecase with black subjects, the frequency of the 1Arg389 variantdid not differ significantly between white patients with heartfailure and white controls. There was no association betweenthe genotype consisting of 2CDel322–325 and 1Arg389 andthe risk of heart failure in white subjects.
Testing for Genetic Stratification of the Populations
The possibility that there was unequal genetic admixture inthe control and patient populations, which could have resultedin a spurious association in black subjects,15 was exploredby means of genotyping at nine highly polymorphic short tandem-repeatloci (Figure 2 and Table 4). Since all subjects were from thesame geographic area and associations were sought within racialgroups, the likelihood of such stratification of the populationswas considered a priori to be low. There were no significantdifferences between black controls and black patients with heartfailure in the frequencies of these markers (Table 4 and Figure 2),indicating that genetic stratification does not accountfor our finding of an association.
Figure 2. Multiple PCR Detection of Short Tandem-Repeat Alleles.
The middle two lanes are ladders that represent all possible alleles from nine short tandem-repeat loci. Each multicolored lane represents fluorescence output from a single patient, which is scored by a computer algorithm. The red signals are molecular-size markers. The results shown are representative of output from a single gel.
Table 4. Frequencies of Short Tandem-Repeat Alleles in Black Controls and Black Patients with Heart Failure.
Testing for Survivor Effect
Finally, the unlikely possibility that the results in blacksubjects were biased by early death attributable to genotype(i.e., a "survivor effect") was considered in four analyses.Contingency tables were used to assess the relations betweengenotype and the age at onset of heart failure, genotype anddistribution of left ventricular ejection fraction, and genotypedistribution at enrollment. Survival analysis was used to testfor an association between genotype and survival after enrollment.Subjects with the various 2C-adrenergic–receptor genotypesdid not differ in terms of age at the time of enrollment inthe study (data not shown). However, the odds ratio for theonset of heart failure before 40 years of age among carriersof 2CDel322–325 as compared with subjects who were homozygousfor the wild-type 2C-adrenergic receptor was 4.07 (95 percentconfidence interval, 1.25 to 13.30; P=0.02). Further analysisused the median left ventricular ejection fraction among allblack patients with heart failure (22.0 percent) to define twogroups with different predicted mortality rates.19 The oddsratio for a left ventricular ejection fraction of 22.0 percentor lower among patients who were homozygous for 2CDel322–325as compared with those who were homozygous for the wild-type2C-adrenergic receptor was 3.63 (95 percent confidence interval,1.17 to 11.22; P=0.03). Furthermore, Kaplan–Meier survivalanalysis indicated that the survival distribution after enrollmentdid not vary according to the 2C-adrenergic–receptor genotype(P=0.23). These results do not suggest the influence of a survivoreffect and support the conclusion that it is the 2CDel322–325allele, as opposed to the wild-type 2C-adrenergic receptor,that is associated with the heart-failure phenotype.
Discussion
In this study, we identified genetic variants of the 1-adrenergicreceptor and the 2C-adrenergic receptor that jointly representa major risk factor for the development of heart failure. Inblack subjects, among whom the 2CDel322–325 and 1Arg389polymorphisms are relatively common, the 2CDel322–325genotype alone represented some degree of risk (odds ratio forheart failure, 5.65), whereas the 1Arg389 genotype alone wasnot associated with heart failure. However, when the two polymorphismsoccurred together in the homozygous state, the risk was substantialand significant, with an adjusted odds ratio of 10.11. Giventhe low prevalence of the 2CDel322–325 polymorphism amongthe white subjects,10 we did not expect to find a significantassociation in this racial group after further stratificationaccording to 1-adrenergic–receptor genotype. Nevertheless,among the white subjects, the frequency of the 2CDel322–325allele was indeed greater among patients with heart failurethan among controls. On the basis of this observation and themolecular properties of the 2CDel322–325 and 1Arg389 receptorsthat have been delineated in transfected cells, we suggest thatthe findings for this two-locus genotype in black subjects aremost likely applicable to the white population as well, butthe extent of the risk in this racial group remains less welldefined.
We explored these two genes as candidate risk factors for heartfailure because of the results of a number of basic studiesas well as studies in animals and humans. 2-Adrenergic receptorsexpressed on presynaptic cardiac sympathetic nerves in humansinhibit the release of the neurotransmitter norepinephrine.8Studies of mice in which the genes for 2A-adrenergic receptorsand 2C-adrenergic receptors have been inactivated indicate thatthe 2C-adrenergic receptor inhibits norepinephrine release underbasal conditions (i.e., with low stimulation frequencies).9Severe cardiomyopathy develops in such mice.9 These studiesthus suggest that factors that depress 2C-adrenergic–receptorfunction, leading to sustained norepinephrine release, mightrepresent factors predisposing persons to the development ofheart failure. The human 2C-adrenergic–receptor polymorphismDel322–325 results in the deletion of four amino acidswithin a G-protein–coupling domain, which greatly decreasesthe function of these receptors (by approximately 85 percent)in transfected cells.10
The 1-adrenergic receptor is the predominant -adrenergic receptorexpressed on the cardiomyocyte and is responsive to circulatingepinephrine and to local norepinephrine derived from cardiacsympathetic nerves.1,2 In rodents, sustained activation of 1-adrenergicreceptors from infusions of -agonists results in hypertrophy,20and transgenic cardiac overexpression of 1-adrenergic receptorscauses progressive cardiomyopathy and heart failure.21,22 Wetherefore considered the 1Arg389 receptor as a possible riskfactor for heart failure, since it results in an increase ofapproximately 200 percent in agonist-stimulated activity intransfected cells as compared with the 1Gly389 receptor.13
Our results revealed a substantial risk of heart failure inblack subjects who were homozygous for both polymorphisms. Theinteraction between the two variants is most likely attributableto the fact that the receptors represent two critical signal-transductionpathways in series: local norepinephrine production and norepinephrine-inducedactivation of a target receptor. The synergistic, rather thansimply additive, nature of the interaction may derive from thefact that activation of receptors that couple to G proteinsinvolves marked signal amplification.23,24 As more polymorphismsof genes within multistep pathways are detected and characterized,other examples of such interactions may become apparent.
Our study raises a number of provocative questions regardingthe potential clinical usefulness of determining these genotypesin patients with heart failure or left ventricular hypertrophyand in asymptomatic persons without evidence of cardiac pathophysiology.Given the magnitude of the findings, and the signaling propertiesof these variant receptors in vitro, the presence of this specifictwo-locus genotype may indicate the need for targeted pharmacologictherapy with 2-adrenergic–receptor agonists, -adrenergic–receptorantagonists, or both. The current study was not designed toascertain these potential effects of genotype on the responseto treatment. Clinical studies with 2-adrenergic–receptoragonists such as clonidine have not shown a consistent improvementin indexes of cardiac output.25,26,27,28,29 The observed heterogeneityin agonist response may have been caused by the presence insome subjects of the 2C-adrenergic–receptor polymorphism.Although -adrenergic–receptor antagonists have been shownto be efficacious in the treatment of heart failure, there isnevertheless a broad range of responsiveness, and even in thosewho ultimately benefit, a prolonged and complex period of titration(two to four months) is required.7
Patients with the combined 2CDel322–325 and 1Arg389 genotypemay represent a subgroup of patients with a differential responseto treatment, and thus genotyping at these loci could be usedto tailor pharmacologic therapy to those with the greatest likelihoodof having a favorable outcome. Indeed, it could be argued thatsuch persons might benefit from treatment at early stages ofthe syndrome, even if they have relatively preserved left ventricularejection fraction and minimal symptoms, since they may be atthe greatest risk for progression. A similar approach mightalso be indicated in persons with asymptomatic left ventricularhypertrophy, with the objective of halting the transition toclinical heart failure. Finally, one must consider whether personswithout left ventricular hypertrophy or heart failure who arehomozygous for both polymorphisms and are therefore at riskfor heart failure might benefit from prophylaxis. Clinical studieswill be required in order to establish whether specific pharmacologictherapy can modify the risk of heart failure, the transitionof hypertrophy to heart failure, or the decompensation of stableheart failure in those who are homozygous for 2CDel322–325and 1Arg389.
Supported by grants (HL-52318 [Specialized Centers of Researchin Heart Failure], ES-06096, HL-22619, and HG-00040) from theNational Institutes of Health; and by the American Heart Association(Ohio Valley Affiliate).
Dr. Liggett was formerly a consultant to Orchid BioSciences.
We are indebted to Kari Brown for adrenergic-receptor genotyping,to Doug Binzler and Carrie Seaman for short tandem-repeat genotyping,and to Nancy McGuire for the collection of clinical data.
Source Information
From the Divisions of Pulmonary Medicine (K.M.S., S.B.L.) and Cardiology (L.E.W.) and the Departments of Medicine and Molecular Genetics (S.B.L.), University of Cincinnati College of Medicine, Cincinnati; and the Department of Epidemiology, University of Michigan, Ann Arbor (A.M.L., S.L.R.K.). Drs. Small and Wagoner contributed equally to the article.
Address reprint requests to Dr. Liggett at the University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267-0564, or at stephen.liggett{at}uc.edu.
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1-adrenergic receptors. In transfected cells, a polymorphic 
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