Correspondence

Polymorphisms of Adrenergic Receptors and the Risk of Heart Failure

N Engl J Med 2003; 348:468-470January 30, 2003

Article

To the Editor:

The interesting study by Small et al. (Oct. 10 issue)1 showed that two potentially synergistic adrenergic-receptor polymorphisms are associated with a risk of congestive heart failure. Since this may indeed give rise to genotype-targeted intervention studies, one important point deserves attention. Although the polymorphism involving the substitution of glycine for arginine at position 389 (Arg389Gly) of the β₁-adrenergic receptor has clearly been shown to be functional in vitro, data on its consequences in vivo are conflicting.2 Moreover, there is high sequence variability in the gene encoding the β₁-adrenergic receptor, with at least 18 single-nucleotide polymorphisms leading to seven amino acid exchanges.3 Thus, Arg389Gly is but one variation of the gene. Another polymorphism in the extracellular amino terminal, one involving the substitution of glycine for serine at position 49 (Ser49Gly), has been shown to affect receptor sensitivity and down-regulation to agonists in vitro,4 resting heart rate in persons with hypertension,5 and the risk of death in persons with congestive heart failure.6

In the study by Small et al., the variant of the α_2C-adrenergic receptor involving the deletion of four amino acids (α_2CDel322–325), when compared with the β₁-adrenergic–receptor variant, conferred the majority of the risk of heart failure, and there was an apparent difference between black and white subjects. These findings, and the conflicting findings reported by others so far, raise the question whether consideration of haplotypes of the β₁-adrenergic–receptor gene instead of single-nucleotide polymorphisms could help explain the results. It would be most helpful if the authors were able to provide data on the functional Ser49Gly variant, on possible other polymorphisms in the receptor genes, and on haplotype distribution.

Christian Meisel, M.D.
Karla Köpke, Ph.D.
Ivar Roots, M.D.
Humboldt University of Berlin, 10098 Berlin, Germany
christian.meisel@charite.de

6 References

1. 1

   Small KM, Wagoner LE, Levin AM, Kardia SLR, Liggett SB. Synergistic polymorphisms of β₁- and α_2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 2002;347:1135-1142
   Full Text | Web of Science | Medline

2. 2

   Jones A, Montgomery H. The Gly389Arg beta-1 adrenoceptor polymorphism and cardiovascular disease: time for a rethink in the funding of genetic studies? Eur Heart J 2002;23:1071-1074
   CrossRef | Web of Science | Medline

3. 3

   Podlowski S, Wenzel K, Luther HP, et al. β₁-Adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? J Mol Med 2000;78:87-93
   CrossRef | Web of Science | Medline

4. 4

   Levin MC, Marullo S, Muntaner O, Andersson B, Magnusson Y. The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem 2002;277:30429-30435
   CrossRef | Web of Science | Medline

5. 5

   Ranade K, Jorgenson E, Sheu WH, et al. A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet 2002;70:935-942
   CrossRef | Web of Science | Medline

6. 6

   Borjesson M, Magnusson Y, Hjalmarson A, Andersson B. A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J 2000;21:1853-1858
   CrossRef | Web of Science | Medline

To the Editor:

We commend Small et al. on their intriguing study. It is unclear, a priori, how many subjects are necessary to determine accurately the attributable risk associated with a single genetic polymorphism, but it is clear that this study had too few. Complex disease phenotypes are determined by the interplay of multiple genetic loci and environmental factors. Determining the quantitative contribution of a specific, common polymorphism requires large study populations and carefully selected controls.1

The conclusions drawn by Small et al. are based on analysis of the pool of black subjects, in which there were as many subjects heterozygous for the α_2CDel322–325 allele as there were subjects homozygous for this allele (and thus was not in Hardy–Weinberg equilibrium). Risk determinations in such pools are likely to be inaccurate. The authors determined risk by comparing patients who had heart failure with healthy volunteers. Genetic risk factors that distinguish patients with idiopathic dilated cardiomyopathy from their siblings with hypertension who do not have heart failure, or that distinguish patients who have ischemic heart failure from those who have ischemia without heart failure, would have greater clinical significance.

Michael L. Maitland, M.D., Ph.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Mardi Gomberg-Maitland, M.D.
Mount Sinai Medical Center, New York, NY 10021

1 References

1. 1

   Vineis P, Schulte P, McMichael AJ. Misconceptions about the use of genetic tests in populations. Lancet 2001;357:709-712
   CrossRef | Web of Science | Medline

To the Editor:

The interaction reported by Small et al. between variants of the β₁- and α_2C-adrenergic receptor genes in the risk of congestive heart failure is an intriguing example of the promise of molecular genetics for disease control.1 Will this study lead to “early preventive measures,” or will the results not be replicated, as in the case of many other associations, because of problems in study design or because of chance?2 We are concerned about the possible effect of selection bias on the results. The participation rates in this study are not specified, and the controls (blood donors and persons who responded to newspaper advertisements) may not have been representative of the population at risk. Indirect evidence of bias is that the control-only odds ratio (which has an expected value of 1 when variation in two genes occurs independently) was 0.37 in all the subjects and 0.39 in the black subjects. Therefore, selection bias may have inflated the observed interaction effect. Furthermore, the proportion of subjects with heart failure who were taking beta-blockers at enrollment differed between blacks and whites (33.3 percent and 60.5 percent, respectively). If variants in either gene (or their combination) affected the response to beta-blocker therapy, eligible persons with heart failure might have been selected differentially according to race, resulting in a biased estimate of interaction according to race.

Julian Little, Ph.D.
Marta Gwinn, M.D., M.P.H.
Muin Khoury, M.D., Ph.D.
Centers for Disease Control and Prevention, Atlanta, GA 30341
jlittle1@cdc.gov

2 References

1. 1

   Collins FS, McKusick VA. Implications of the Human Genome Project for medical science. JAMA 2001;285:540-544
   CrossRef | Web of Science | Medline

2. 2

   Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002;3:391-397
   CrossRef | Web of Science | Medline

Author/Editor Response

Meisel et al. suggest that data on β₁-adrenergic–receptor haplotypes might provide additional predictive power. Except for the polymorphism at position 49, the other reported variants have been found in only a few persons, with apparent allele frequencies of less than 0.05.1 The in vitro phenotypes of the Ser49Gly polymorphism include enhanced agonist-promoted receptor down-regulation.2,3 The allele frequency of the Gly49 polymorphism is about 15 percent in blacks and whites4 and is in strong linkage disequilibrium with Arg389 (P=0.003). The β₁-adrenergic–receptor Gly389 polymorphism alone was not associated with heart failure, and the estimated frequencies of β₁-adrenergic–receptor haplotypes were nearly identical between subjects with heart failure and controls (P>0.98 in both whites and blacks). The number of subjects with the three-locus genotype combination was too low to assess risk meaningfully, and therefore a combined effect of β₁-adrenergic–receptor haplotype and the α_2C-adrenergic–receptor polymorphism cannot be ruled out.

We agree with Maitland and Gomberg-Maitland that other studies are needed to confirm our observations as well as to assess potential associations with specific phenotypes. We disagree with the notion that the absence of Hardy–Weinberg equilibrium (i.e., the presence of disequilibrium) for the α_2CDel322–325 polymorphism in the black subjects with heart failure is an indication of inaccuracies in the data. On the contrary, unfavorable conditions for equilibrium are likely to be imposed by biologically relevant genetic variations. Thus, disequilibrium is expected and provides further evidence of the importance of the polymorphism.5

Little et al. question whether the cohorts were representative. Recently, we noted that the frequencies of the two polymorphisms in DNA from the Coriell Cell Repositories are nearly identical to those in the black control population we described. And, in our study, we carefully explored the possibility of population stratification between the control and patient cohorts within each racial group by assessing the frequencies of short-tandem repeats and found none. With respect to the control-only odds ratio in blacks, we should point out that the 95 percent confidence interval is 0.07 to 1.89, and thus any deviation from the underlying assumptions used in the interpretation of our study is not statistically significant. Finally, we see no reason why the lower frequency of use of beta-blockers by black subjects with heart failure on enrollment than by white subjects with heart failure introduces a bias concerning our primary conclusion. Patients were classified as having heart failure regardless of the response to beta-blockers, and all had ejection fractions below 35 percent before or during therapy. Because the frequency of the α_2CDel322–325 polymorphism is so low in whites, we carried out a separate analysis for each racial group.

Sharon L.R. Kardia, Ph.D.
Albert M. Levin, M.P.H.
University of Michigan School of Public Health, Ann Arbor, MI 48109-2029

Stephen B. Liggett, M.D.
University of Cincinnati College of Medicine, Cincinnati, OH 45267-0564
stephen.liggett@uc.edu

5 References

1. 1

   Podlowski S, Wenzel K, Luther HP, et al. β₁-Adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? J Mol Med 2000;78:87-93
   CrossRef | Web of Science | Medline

2. 2

   Rathz DA, Brown KM, Kramer LA, Liggett SB. Amino acid 49 polymorphisms of the human Beta 1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 2002;39:155-160
   CrossRef | Web of Science | Medline

3. 3

   Levin MC, Marullo S, Muntaner O, et al. The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem 2002;277:30429-30435
   CrossRef | Web of Science | Medline

4. 4

   Moore JD, Mason DA, Green SA, Hsu J, Liggett SB. Racial differences in the frequencies of cardiac β₁-adrenergic-receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat 1999;14:271-271
   CrossRef | Medline

5. 5

   Nielsen DM, Ehm MG, Weir BS. Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63:1531-1540
   CrossRef | Web of Science | Medline

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