Published online before print April 24, 2006, doi: 10.1161/01.HYP.0000217972.80731.ef
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(Hypertension. 2006;47:1140.)
© 2006 American Heart Association, Inc.
Original Articles |
Do Allelic Variants in 
2A and 2C Adrenergic Receptors Predispose to Hypertension in Blacks?
From the Divisions of Hypertension (J.-L.L., D.L., R.G.V., W.V.), Endocrinology (R.J.A.), and Cardiology (R.M.C.), Department of Internal Medicine, and Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas.
Correspondence to Ronald G. Victor, Hypertension Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8586. E-mail Ronald.Victor{at}UTSouthwestern.edu
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Abstract |
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Sequence variations in the human
2 adrenergic receptor genes (ADRA2A and ADRA2C) have been implicated as a cause of hypertension in blacks. Although certain alleles are selectively enriched in blacks, their association with hypertension is based on small convenience samples and has not been evaluated in larger populations. From a stratified random population sample of 3398 individuals (52% blacks), we obtained DNA samples together with an in-home health interview, 10 in-home measurements of blood pressure, and cardiac MRI. We tested for associations among hypertension, untreated blood pressure, and parameters of hypertensive heart disease with 2 alleles, a DraI restriction fragment length polymorphism in the ADRA2A gene and a deletion of residues 322 to 325 in the ADRA2C gene. Although both alleles were selectively enriched in this black population, we found no association of either allele with hypertension, untreated blood pressure, or any of the cardiac function parameters. In a logistic model that controlled for age, body mass index, diabetes, and smoking, the adjusted odds ratio (OR) for hypertension was 1.0 (95% CI, 0.8 to 1.2), and 1.0 (95% CI, 0.9 to 1.2) for ADRA2A and ADRA2C variant alleles. In subjects not receiving prescription blood pressure medication, neither of these alleles, alone or in combination, was predictive of blood pressure, heart rate, left ventricular mass, cardiac output, systemic vascular resistance, or aortic compliance. Both the DraI restriction fragment length polymorphism in ADRA2A and the ADRA2C (Del 322 to 325) can be excluded as major candidate alleles for hypertension in blacks.
Key Words: hypertension, genetics • receptors, adrenergic alpha • polymorphisms • sympathetic nervous system
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Introduction |
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In blacks, hypertension is more prevalent, more severe, and causes more disability and death than in other ethnic groups in the United States.1–6 Despite numerous hypotheses, a genetic underpinning to this excessive hypertension has been difficult to define.7 Two allelic variants in the human
2 adrenergic receptor (AR) genes are selectively enriched in blacks and seem to impair receptor function.8,9 In mice, 2A and 2C AR subtypes decrease sympathetic drive to the heart and peripheral circulation,10 such that loss-of-function mutations might predispose to hypertension.
The first allele, a DraI restriction fragment length polymorphism (RFLP) in the 3'-untranslated region of the ADRA2A gene, is 50% more common in blacks than whites.11 The variant allele produces a less stable transcript, which could increase sympathetic drive and blood pressure (BP).8 This allele has been associated with increased hypertension prevalence11 and increased cardiovascular reactivity in normotensive young adults.8,12 The second variant allele, which is 10-fold more common in blacks than non-blacks, encodes a 4-amino acid deletion in the human 2C AR (Del 322 to 325).9 In heterologous systems, the 2cDel322-325 receptor displays depressed agonist-induced coupling to inhibitory G proteins,9 which would impair feedback inhibition of catecholamine release and might predispose to hypertension. The 2cDel322-325 allele has been associated with elevated basal BP and exaggerated yohimbine-induced increases in BP and heart rate in healthy young adults,13 as well as a 5-fold increased risk of heart failure in blacks.14
The unanswered question is whether the reduced function of the encoded transcripts and receptor proteins seen with model systems impair human BP regulation sufficiently to cause hypertension. Because the previous studies were limited by small convenience samples, here we tested for associations between these candidate alleles, both alone and in combination, with hypertension, untreated BP, and measures of hypertensive heart disease using a random population sample enriched with blacks.
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Methods |
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Human Subjects
Subjects were drawn from the Dallas Heart Study, a stratified random sample of 6101 county residents, with equal numbers of black and non-black women and men from the estimated 1.43 million adults aged 18 to 65 years in Dallas County, Tex, between July 2000 and January 2002; the sampling methods and validation have been published.15 The study was approved by the institutional review boards at both the University of Texas Southwestern Medical Center at Dallas and Research Triangle Institute (who managed the survey staff). Subjects gave informed written consent to participate in each of the data collection visits and to allow their DNA to be analyzed for potential associations with cardiovascular disease. The study was conducted in accordance with the principles of the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46.
The present analyses are restricted to the 3398 subjects ages 30 to 65 who provided DNA samples; allelic determination for 2A AR was successful in 3271 subjects, including 1696 blacks, and allelic determination for 2C AR was successful in 2830 subjects, including 1458 blacks. In addition to isolating DNA from peripheral lymphocytes, we obtained multiple sets of BP and heart rate measurements on 3 separate days. Subjects were interviewed in their homes by ethnically congruent surveyors with a comprehensive computer-assisted, structured health questionnaire to assess hypertension treatment status and to obtain sociodemographic data and information on environmental exposures known to influence BP. These included age, body mass index (BMI), diabetes, education, and income (Table 1). To assess the time-integral burden of BP on the heart, a total of 1336 untreated black participants underwent thoracic MRI using methods described previously.15,16 Measures included left ventricular (LV) mass and function, as well as aortic compliance.17 Cardiac output and systemic vascular resistance were calculated from the MRI experiments. LV hypertrophy was defined as LV mass at the 97.5 percentile of gender-specific, normotensive, nondiabetic, nonobese reference groups.16
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Measurement of BP
BP was measured with the first electronic oscillometric sphygmomanometer (Welch Allyn, Series 52 000) to be rigorously validated against mercury sphygmomanometry using the British Hypertension Society protocol.18,19 All of the study personnel were trained by 1 investigator (R.G.V.) in the appropriate technique for accurate measurement of BP. In each subject, BP was measured after 10 minutes of rest with an appropriately sized cuff placed on a bare right arm at heart level with the subject seated in a straight-back chair with the legs uncrossed and the feet on the floor. To minimize the alerting reaction to cuff inflation, 5 sequential measurements were taken at 1-minute intervals. To obtain an accurate assessment of a subject’s usual BP, this same measurement protocol was performed on 2 home visits, separated by a median of 17 days. The data reported in this article are the mean of the last 3 BPs from both home measurement periods. Systemic vascular resistance was calculated from BP measured at the time of the MRI examination (Table 2). Hypertension was defined as a mean systolic BP 
140 mm Hg, diastolic BP 90 mm Hg, or current treatment with prescription antihypertensive medication.20
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Genotyping
Genomic DNA was isolated from peripheral blood using the Puregene kit (Gentra System); oligonucleotides were purchased from Integrated DNA Technologies. All of the sequencing was performed using an ABI 3730 automated DNA sequencing instrument and Big Dye Version 3.1 dye terminator chemistry (Applied Biosystems).
The DraI RFLP in the 3'-untranslated region of the ADRA2A gene was scanned using the allelic discrimination mode of the ABI 7900HT real-time polymerase chain reaction (PCR) instrument. Primers and probes were obtained from ABIs Assay-by-Design custom service. The assay was validated by DraI digestion of several samples with each genotype.
The 12-bp in-frame deletion (Del322-325) allele of ADRA2C was identified by a size fractionation assay. A DNA fragment spanning the polymorphic region was PCR amplified and fluorescence labeled using a 6-carboxytetrafluorescein–labeled sense primer 5'-6-carboxytetrafluorescein-GTCTACGCGCGCATCTACCGAGTGGCCAAG-3' and unlabeled antisense primer 5'-CCCATGACCACAGCCAGCACAAAGGTGAAG-3'. Thermocycling parameters were the same as for ADRA2C. Amplicon sizes were determined using an ABI 3100 automated DNA sequencer without purification of the PCR product. The results of the fragment analysis were verified by directly sequencing PCR fragments amplified using unlabeled primers.
Statistical Analyses
SAS/STAT software, version 9.1, was used for all of the analyses. Because the alleles of interest are enriched in blacks and to eliminate confounding by ethnicity, all of the explanatory models were restricted to non-Hispanic blacks.
In tables comparing wild-type and allelic variants for selected characteristics, P values were obtained from ANOVA, using wild type as the reference category. The linear regression models for systolic and diastolic BP test the significance of the additive effect of each variant allele when controlling for gender, age, BMI, diabetes, and smoking. Treated hypertensives were excluded from the BP models. The logistic regression models for hypertension tested the significance of the additive effect of each variant allele when controlling for age, gender, BMI, diabetes, and smoking. All of the individuals were included in the hypertension models regardless of antihypertensive treatment. To further examine the potential effects of age and gender, Cochran-Mantel-Haenszel 
2 tests were performed and stratified by age and gender. Fisher’s exact test was used to examine potential associations between genotype and family history of hypertension. Alternative regression models, with the allelic effects entered as a 3-level categorical variable or as a 2-level categorical variable (homozygotes versus others) were not qualitatively different from those that estimated the additive effect of each variant allele.
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Results |
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Characteristics of the Study Population
Table 1 shows sociodemographic and medical characteristics derived from the 1760 non-Hispanic black, 1001 white, and 570 Hispanic study participants who provided DNA samples. The striking ethnic differences included: (1) marked socioeconomic disadvantage among both minority groups, and (2) dramatically higher prevalence rates of hypertension and LV hypertrophy among blacks compared with whites or Hispanics. Table 2 presents detailed genotype-specific information on quantitative traits among the subset of black participants who were not receiving antihypertensive medication at the time of the study.
ADRA2A: DraI 6.3-kb RFLP as a Candidate Allele for Hypertension in Blacks
The variant ADRA2A allele (Figure 1A) was prevalent in all 3 of the ethnic groups but was more common in blacks and Hispanics (Figure 1B). Consistent with previous reports,8,11,12 allele frequencies were 0.31 and 0.18 in blacks and whites, respectively, and were in Hardy-Weinberg equilibrium. Of the 1696 blacks successfully genotyped, there were 714 heterozygotes and 165 homozygotes for the variant allele.
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), heterozygotes (
), and homozygotes (
) for the variant allele, with numbers of subjects on or near respective bar sections. (C) logistic regression model showing adjusted ORs and 95% CIs for hypertension in blacks. (D) systolic BP plotted as a function of age in untreated black individuals carrying only the wild-type allele (
) or 1 or 2 copies of the variant allele (•).
Among these black participants, hypertension was present in 43% of those with only the wild-type allele, in 42% of heterozygotes, and in 41% of homozygotes for the variant allele. In a logistic regression model, the variant allele was not a significant predictor of hypertension (Figure 1C): adjusted OR, 1.0 (95% CI, 0.8 to 1.0; P=0.86). There was no significant association between genotype and hypertension in an overall 2 analysis (P=0.90) or when stratified by age and gender. No association was found between genotype and family history of hypertension (P=0.89). In a linear regression model of untreated systolic BP, the additive effect of the variant allele (0.1±0.4 mm Hg per allele; P=0.91) was not significant (Figure 1D).
ADRA2C: Del322-325 as a Candidate Allele for Hypertension in Blacks
Consistent with previous reports,9 the variant allele (Figure 2A) was much more prevalent in blacks than in non-blacks (Figure 2B). Variant allele frequencies were 0.41 and 0.06, respectively, in blacks and whites and were in Hardy-Weinberg equilibrium.
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Of the 1458 blacks successfully genotyped, there were 694 heterozygotes and 246 homozygotes for the Del322-325 allele. Among these black participants, hypertension was present in 42% of those with only the wild-type allele, in 42% of heterozygotes, and 42% of homozygotes for the variant allele. Logistic regression showed that the variant allele was not a predictor of hypertension (Figure 2C): adjusted OR, 1.0 (95% CI, 0.9 to 1.2; P=0.76). There was no significant association between genotype and hypertension (P=0.89) or stratified by age and gender. No association was found between genotype and family history of hypertension (P=0.27). In a linear regression model of untreated systolic BP, the additive effect of the variant allele (–0.5±1.3 mm Hg; P=0.51) was not significant (Figure 2D).
Combined Analysis of ADRA2A and ADRA2C Alleles With BP and LV Mass
Although these separate analyses failed to demonstrate an association of either candidate allele with hypertension, it is possible that the variant alleles could have additive or synergistic effects when present in combination. Table 3 shows the mean values of systolic and diastolic BP, as well as heart rate and LV mass (adjusted for body surface area) for untreated black participants carrying either the variant 2A AR allele or the variant 2C AR allele alone or in combination. No evidence was found for a dosage effect with any of these parameters in either univariate or multivariate analyses.
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Discussion |
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Two allelic variations in the ADRA2A and ADRA2C genes have attracted considerable attention as predisposing factors to hypertension and hypertensive heart disease in blacks. Using the largest and only population-based sample to study these alleles, we found no evidence to support previously suggested associations between the 2
2 AR alleles alone or in combination with hypertension, untreated BP, or numerous cardiac MRI indices of hypertensive heart disease in blacks.
In mice, 2A ARs are the main subtype of 2 AR that tonically restrain sympathetic outflow from the rostral medulla and play a major role in feedback inhibition of norepinephrine (NE) release from sympathetic varicosities.10 Targeted disruption of the 2 AR gene causes hypertension and tachycardia and impaired baroreceptor reflexes in mice.21 The same phenotype is seen in mice with a point mutation in the 2 AR gene that reduces receptor density in the central nervous system to 20% of normal values.22 Similarly, in humans, the DraI RFLP allele, which is present in 30% of blacks, might decrease 2A AR density and increase sympathetic activity, thereby predisposing to hypertension.8
In 3 independent cohorts of normotensive young adults, the variant ADRA2A allele has been associated previously with multiple indirect indices of heightened sympathetic reactivity to laboratory stressors.8,12 These included augmented increases in heart rate and forearm vascular resistance in response to baroreceptor deactivation, impaired renal sodium excretion in response to baroreceptor activation, increased epinephrine-induced platelet aggregation, augmented exercise-induced sodium excretion from sweat glands, and increased susceptibility to motion sickness. The exaggerated sympathetic reactivity was postulated to constitute an intermediate phenotype for the subsequent development of hypertension.8,12 Indeed, in a small case–control study, this variant allele seemed to be enriched in a hypertensive black clinic sample compared with normotensive black controls: 13 of 82 hypertensive blacks were homozygous for the variant allele compared with only 2 of 59 normotensive blacks.11 In contrast, our present data in a sample of 1696 blacks provide no support for the hypothesis that this variant allele is associated with hypertension. In contrast to mice with decreased 2A AR number,22 our human subjects carrying 1 or 2 copies for the variant ADRA2A allele did not have higher levels of BP, heart rate, cardiac output, or systemic vascular resistance than noncarriers.
Recent studies in both animals and humans have for the first time implicated an important role for 2C ARs in cardiovascular regulation. In mice, 2C ARs modulate NE release during basal levels of sympathetic nerve activity, whereas 2A ARs modulate NE release during only very high levels of sympathetic activation.23 Furthermore, murine 2C ARs modulate epinephrine release from adrenal chromaffin cells, whereas murine 2A ARs do not.24 In response to pressure overload, 2A or 2C AR knockout mice display greater plasma NE levels, cardiac hypertrophy, and cardiovascular mortality compared with wild-type mice.25
In humans, 60% of blacks carry the Del322-325 allele, which encodes a less active 2C AR that has been postulated to predispose to hypertension and hypertensive heart disease.9 In a recent study, baseline and yohimbine-stimulated plasma NE and BP were found to be higher in 11 Del322-325 homozygotes than in 9 heterozygotes and 9 noncarriers.13 However, our data in 246 homozygotes, 694 heterozygotes, and 518 noncarriers show no evidence either that the Del322-325 allele is an independent predictor of hypertension or hypertensive heart disease in blacks or that this allele accelerates the age-dependent increase in BP.
Although these separate analyses failed to demonstrate an association of either candidate 2 AR allele with hypertension, it is possible that the variant alleles could have additive or synergistic effects when present in combination. In this regard, mouse studies have suggested considerable redundancy in 2A and 2C AR regulation of NE release.10,23 Plasma NE levels and LV mass were greatly increased, and LV contractility greatly decreased in 2A/2C AR double-knockout mice compared with a much milder phenotype in 2A AR single-knockout mice and a normal phenotype in 2C AR single-knockout mice.23 We looked carefully but found no evidence to suggest this type of combinatorial genotype–phenotype relation in our human subjects, even among those who were homozygous for the 2 implicated alleles.
The major strengths of our study are the population-based sampling and the comparatively large sample size, including sufficient numbers of untreated black subjects, to examine BP as a quantitative trait and to perform combinatorial analysis. Another strength is the measurement of BP with accurate electronic monitors to reduce observer error. The repeated measurements of home BP on different days together with cardiac and aortic MRI measurements provided a careful evaluation of the time-integral burden of BP on the human cardiovascular system. We also collected extensive information on environmental exposures and other covariates to control for these nongenomic influences in multivariate analyses.
The limitations of our study include the absence of: (1) measurements of NE or sympathetic nerve activity, and (2) provocative maneuvers to assess the dynamic regulation of sympathetic activity, NE, and BP. Nevertheless, the variant alleles were not associated with a high basal heart rate or a high cardiac output state, well-established early hemodynamic signatures of neurally mediated hypertension (or prehypertension) in young adults.26–28 If the variant alleles, indeed, are associated with higher basal rates of NE release in target cardiovascular tissues, such sympathetic overactivity does not seem to contribute in a major way to the development of hypertension in our population. The present data by no means exclude the possibility that the physical and emotional stresses of daily life might evoke exaggerated pressor responses in normotensive or prehypertensive young adults who carry these variant alleles. However, that repeated but transient adrenergic BP surges eventually produce sustained hypertension remains an attractive but unproven theory.29
Perspectives
Other studies have shown that the expression of the 2C AR may be modestly influenced by haplotype, but almost half of the Del322-325 alleles were found in 1 of 8 haplotypes.30 Consequently, it is likely that our results apply to the majority of blacks, yet we cannot exclude any association between the variant 2 AR alleles and BP within small subpopulations. Taken together, the present data strongly suggest that both the DraI RFLP in the 2A AR and the Del322-325 variant in the 2C AR can be excluded as major candidate alleles for hypertension in blacks. Using the same approach and database to study other alleles that are selectively enriched in blacks, our group recently reported a positive association of hypertension with allelic variants of the CORIN gene,31 which is involved in natriuretic peptide processing. In contrast, we found no association of the epithelial sodium channel T594M allele with hypertension or antihypertensive response to amiloride.32 The application of high-throughput genotyping to an extensively phenotyped multiethnic population sample constitutes an important new strategy for better defining the elusive genetic contributions to primary human hypertension.
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Acknowledgments |
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This research was funded by a grant to Dr Victor from the National Institute of Drug Abuse (R01 DA10064) and by a center grant from the Donald W. Reynolds Foundation. We thank all of the Dallas Heart Study investigators who contributed to the collection and construction of the database and Dr Jonathan Cohen, Dr Bill Crider, and Tommy Hyatt for conducting the high-throughput genotyping in the McDermott Core Genotyping Facility.
Received December 28, 2005; first decision January 17, 2006; accepted March 7, 2006.
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