CORRESPONDENCE: RESEARCH CORRESPONDENCE
 2cDel322-325 and ß1Arg389 Adrenergic Polymorphisms Are Not Associated With Reduced Left Ventricular Ejection Fraction or Increased Left Ventricular Volume
Russell M. Canham, MD, MCS,
Sandeep R. Das, MD, MPH,
David Leonard, PhD,
Shuaib M. Abdullah, MD,
Sameer K. Mehta, MD,
Anne K. Chung, BS,
Jia-Ling Li, MD,
Ronald G. Victor, MD,
Richard J. Auchus, MD, PhD and
Mark H. Drazner, MD, MSc*
* University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 (Email: Mark.Drazner{at}UTSouthwestern.edu).
To the Editor: Polymorphisms in adrenergic receptors are potential risk factors for developing systolic heart failure (HF) presumably via modulation of sympathetic nervous system activity (1). Two such polymorphisms ( 2cDel322-325 and ß1Arg389) appear to have adverse synergistic effects, with the 2cDel322-325 receptor increasing synaptic norepinephrine levels via loss of negative feedback and the ß1Arg389 receptor increasing responsiveness to norepinephrine. In a prior study, others demonstrated that African Americans with both of these polymorphisms were at increased risk of HF (1). If this association was robust, we reasoned that these 2 polymorphisms would also be strongly associated with phenotypes that are precursors to systolic HF such as increased left ventricular end-diastolic volume (EDV) and decreased left ventricular ejection fraction (LVEF). The Dallas Heart Study (DHS), a large multiethnic population-based probability sample of Dallas County, afforded the opportunity to test this hypothesis.
The design of the DHS, conducted at 3 sequential visits, has been described including sampling methods and validation (2), assignment of race, and its cardiac magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry protocols (3,4). To determine whether subjects had a history of HF, participants were first asked: "Has a doctor or other health professional ever told you that you had any kind of heart problems or a heart condition?" If they answered "Yes," they were subsequently asked: "Has a doctor or other health professional ever told you that you have congestive HF, an enlarged heart, a weak heart, or cardiomyopathy?" Subjects who answered yes to both questions were classified as having a history of HF. A reduced LVEF was defined as <61% in women and <55% in men as recently reported (4). Gentoypes for ß1Arg389 were ascertained using allelic discrimination (Applied Biosystems, Foster City, California) and for 2cDel322-325 by a size fractionation assay. For the latter, we amplified the ADRA2C gene from genomic DNA using oligonucleotides 5'-FAM-GTCTACGCGCGCATCTACCGAGTGGCCAAG-3' + antisense primer 5'-CCCATGACCACAGCCAGCACAAAGGTGAAG-3'. Amplicons were size-fractionated on an ABI 3100-automated DNA sequencer. Informed consent was obtained, and the Institutional Review Board of University of Texas Southwestern Medical Center approved this protocol.
We restricted our analyses to participants who were white or black, had available genotype data at the 2 loci of interest, and underwent cardiac MRI (n = 1,861). We classified subjects into 1 of 4 mutually exclusive categories (1): group 1: heterozygote or wild-type at both loci; group 2: heterozygote or wild-type at 2cDel322-325 and homozygote at ß1Arg389; group 3: homozygote at 2cDel322-325 and heterozygote or wild-type at ß1Arg389; and group 4: homozygote at both loci. Data were analyzed using the SAS (version 9.1, SAS Corp., Cary, North Carolina) statistical software package. Continuous variables are presented as mean ± SD. Associations between genotype and categorical variables were tested using Fisher exact test. Group differences in means of B-type natriuretic peptide were tested using the non-parametric Kruskal-Wallis test. Group differences in means of other continuous variables were tested using the 1-way analysis of variance F-test of the group effect. Post hoc we calculated the power to detect a 4-point LVEF difference and a 5 ml/m2 difference in EDV/body surface area (BSA) between groups 1 and 4 (see the preceding text). For all analyses, 2-tailed p values <0.05 were considered statistically significant.
Our study cohort included 1,121 African-American and 740 white subjects (58% and 51% women, respectively) with a mean age of 45 ± 10 years. The allele frequency of 2cDel322-325 was 0.40 in African Americans and 0.06 in whites, yielding 17% and 0.8% homozygous, respectively. The allele frequency of ß1Arg389 was 0.58 in African-American and 0.72 in white subjects, yielding 35% and 52% homozygous, respectively. In African Americans, the prevalence of diabetes was 13%, hypertension 42%, and obesity (body mass index  30 kg/m2) 51%.
When African-American subjects were classified into 1 of 4 groups (1), we found no association between genotype group with either B-type natriuretic peptide levels, self-reported history of HF, or measures of left ventricular structure and function (Fig. 1). When these analyses were repeated in white subjects, recognizing the lower allele frequency of 2cDel322-325, there again was no association of genotype group and cardiac traits (data not shown). In African Americans, the power to detect a 4-point decrease in LVEF in group 4 versus group 1 (from 74% to 70%) was 94%, and the power to detect a 5-point increase in EDV/BSA between these 2 groups (from 51 to 56 ml/m2) was 81%.
In this study, we attempted to replicate the putative association of 2cDel322-325 and ß1Arg389 with increased risk of systolic HF in African-American subjects (1). Although studies of white Italian (5) and Japanese patients (6) have demonstrated no association of these polymorphisms and risk of HF, to our knowledge no replication in African-American patients has been conducted. We found very similar allele frequencies of 2cDel322-325 and ß1Arg389 as previously reported (1). However, we were unable to demonstrate an association of these 2 alleles with reduced LVEF or increased ventricular volume, traits that are considered precursors to systolic HF. Further, there was no association of genotype with levels of B-type natriuretic peptide or self-reported history of HF. In total, these data question the strength of the association of these alleles and risk of developing systolic HF.
The main limitation of our study is that the DHS is a healthier population-based cohort as compared with the original study cohort comprised of patients with symptomatic HF (1). Nevertheless, we had 94% power to detect an association of the polymorphisms with a 4-point decrement in LVEF and 81% power to detect an increase in EDV/BSA of 5 ml/m2. Other polymorphisms in 2c-adrenergic receptor have been shown to influence its expression, thereby potentially modulating the cardiomyopathic properties of 2cDel322-325 (7). Although we did not genotype our subjects for these additional polymorphisms and thus cannot perform a haplotype-based analysis, it nevertheless was important to test the strength of the previously reported association of 2cDel322-325 and ß1Arg389 with risk of HF in African-Americans subjects.
In a large population cohort of African-American subjects, we found there was no association between the combination of 2cDel322-325 and ß1Arg389 and traits commonly accepted to be precursors of systolic HF.
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Footnotes
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Please note: The Dallas Heart Study is funded by a center grant from the Donald W. Reynolds Foundation. Dr. Mark Drazner was the recipient of a Clinical Scientist Development Award and Anne Chung was the recipient of a Doris Duke Research Fellow grant, both from the Doris Duke Charitable Foundation (New York, New York). Dr. Auchus has reported that he is on a speakers' bureau for Pfizer, Inc. and Columbia Laboratories and a consultant for Cougar Biotechnology.
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References
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- Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of ß1- and 2c-adrenergic receptors and the risk of congestive heart failure N Engl J Med 2002;347:1135-1142.[Abstract/Free Full Text]
- Victor RG, Haley RW, Willett DL, et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health Am J Cardiol 2004;93:1473-1480.[CrossRef][ISI][Medline]
- Drazner MH, Dries DL, Peshock RM, et al. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas Heart Study Hypertension 2005;46:124-129.[Abstract/Free Full Text]
- Chung AK, Das SR, Leonard D, et al. Women have a higher left ventricular ejection fraction than men independent of their differences in left ventricular volume Circulation 2006;113:1597-1604.
- Metra M, Zani C, Covolo L, et al. Role of ß1- and 2c-adrenergic receptor polymorphisms and their combination in heart failure: a case-control study Eur J Heart Fail 2006;8:131-135.[CrossRef][ISI][Medline]
- Nonen S, Okamoto H, Akino M, et al. No positive association between adrenergic receptor variants of 2cDel322-325, ß1Ser49, ß1Arg389 and the risk for heart failure in the Japanese population Br J Clin Pharmacol 2005;60:414-417.[CrossRef][ISI][Medline]
- Small KM, Mialet-Perez J, Seman CA, Theiss CT, Brown KM, Liggett SB. Polymorphisms of cardiac presynaptic 2c adrenergic receptors: diverse intragenic variability with haplotype-specific functional effects Proc Natl Acad Sci U S A 2004;101:13020-13025.[Abstract/Free Full Text]
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Reduced left ventricular ejection fraction (LVEF) defined as <61% for females and <55% for males (
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