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Hypertension. 2006;48:892-900
Published online before print October 2, 2006, doi: 10.1161/01.HYP.0000244688.45472.95
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(Hypertension. 2006;48:892.)
© 2006 American Heart Association, Inc.

Original Articles

ß-2 Adrenergic Receptor Diplotype Defines a Subset of Salt-Sensitive Hypertension

Luminita Pojoga; Nikheel S. Kolatkar; Jonathan S. Williams; Todd S. Perlstein; Xavier Jeunemaitre; Nancy J. Brown; Paul N. Hopkins; Benjamin A. Raby; Gordon H. Williams

From the Division of Endocrinology, Diabetes, and Hypertension (L.P., N.S.K., J.S.W., G.H.W.), Division of Cardiology (T.S.P.), and Channing Laboratory (B.A.R.), Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass; Centre d’Investigation Clinique (X.J.), Departement de Genetique, Hôpital Européen Georges Pompidou, Paris, France; Departments of Medicine and Pharmacology (N.J.B.), Vanderbilt University Medical Center, Nashville, Tenn; and the Department of Medicine (P.N.H.), University of Utah School of Medicine, Salt Lake City.

Correspondence to Gordon H. Williams, Brigham and Women’s Hospital, Division of Endocrinology, Diabetes, and Hypertension, 221 Longwood Ave, Boston, MA 02115. E-mail gwilliams{at}partners.org


*    Abstract
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 *Abstract
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Two genetic variants of the ß-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin–angiotensin–aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 ß-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The ß-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the ß-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where ß-2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype.


Key Words: ß-2 adrenergic receptor • hypertension • salt-sensitive hypertension • low-renin hypertension • single nucleotide polymorphisms • haplotypes • diplotypes


*    Introduction
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 *Introduction
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 down arrowResults
 down arrowDiscussion
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The ß2-adrenergic receptor (ß2AR) is generally thought to influence blood pressure homeostasis through sympathetic nervous system–mediated effects on vascular tone and cardiac contractility.1 The ß2AR gene is located on the distal segment of the long arm of chromosome 5 (5q33.3 to 34); this region has been identified as a susceptibility locus for blood pressure and hypertension in several genome-wide scans.2–5 Two common, nonsynonymous, coding single nucleotide polymorphisms (SNPs) from this gene, 46G>A (Gly16Arg) and 79C>G (Gln27Glu), have been shown to affect agonist-mediated receptor desensitization and downregulation,6–8 as well as vascular reactivity.9–11 Because of these findings, these and other polymorphisms in the ß2AR gene have been extensively investigated in linkage and association studies with human hypertension, with conflicting results.10–24 As has been observed with other complex diseases, conflicting findings have been the norm in genetic studies of hypertension, particularly when a distant phenotype (eg, hypertension) has been used.25

The interplay of multiple susceptibility genes and environmental factors often hampers efforts to relate a candidate gene to a complex trait, such as hypertension.26 An alternative approach is to divide the hypertensive population into more homogeneous subgroups (intermediate phenotypes) where subjects are required to have the distant phenotype (eg, hypertension) and an intermediate phenotype (eg, blood pressure salt sensitivity).27 We have previously used this strategy to identify genetic determinants of 2 forms of salt-sensitive hypertension, low-renin (LR) and nonmodulating hypertension.28,29 Although most studies suggest that ß2AR activation leads to changes in cardiac or vascular tone, one study raises the intriguing possibility that SNPs in the ß2AR gene may be associated with salt-sensitive hypertension.30 Svetkey et al30 provided preliminary evidence that the ß2AR gene was linked to a subset of black hypertensive patients, in whom blood pressure was salt sensitive. None of the previously cited studies have examined the potential role of ß2AR SNPs in salt-sensitive hypertension.

The use of haplotypes and/or diplotypes is a more recent approach that may help elucidate the relationship between a candidate gene and a trait.31 Haplotypes characterize the linkage disequilibrium pattern of a genetic region more precisely than individual SNPs and capture information regarding interactions between SNPs. This approach was not used in any of the previously cited studies and could be an additional reason for the conflicting reports. Based on the preliminary results from Svetkey et al30 and our approach of using intermediate phenotypes to characterize the role of genetic polymorphisms in complex traits, we determined whether variation in the ß2AR gene was associated with: (1) hypertension per se, (2) blood pressure response to dietary sodium, (3) the 2 major salt-sensitive intermediate phenotypes (LR and nonmodulating hypertension), and (4) the activity of the renin–angiotensin–aldosterone system (RAAS) to gain insight into potential mechanisms. To address the possible confounding effect of ethnicity, we restricted our analysis to white subjects. Positive findings from this study could potentially explain the conflicting results that have been reported when hypertension has been used as the phenotype.


*    Methods
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Subjects and Protocol
Included in this report are 280 hypertensive and 65 normotensive white subjects studied by the Hypertensive Pathotype Group who had the 46G>A and 79C>G ß2AR genotype available. Subjects were recruited from the general population of the Brigham and Women’s Hospital (n=107), Hospital Broussais in Paris, France (n=83), University La Sapienza in Rome, Italy (n=23), University of Utah (n=113), and Vanderbilt University (n=19). Of the 345 total subjects, there were 212 with no other sibling included, 112 from sibling pairs, and 21 from trios. The institutional review board of each institution approved the study, and all of the subjects gave written informed consent before enrollment. Hypertension was defined as a seated diastolic blood pressure of ≥100 mm Hg off antihypertensive medication, ≥90 mm Hg while taking ≥1 medication, or treatment with ≥2 medications. Assessment was made on an unrestricted sodium diet. Subjects with hypertension requiring >4 medications were excluded. Normotensive subjects were required to have no family history of a first-degree relative diagnosed with hypertension before 60 years of age.

All of the subjects had a screening history and physical and laboratory examination. Subjects with a history of diabetes mellitus, coronary artery disease, stroke, or any significant medical or psychiatric illnesses were excluded. Subjects with secondary forms of hypertension, obesity (body mass index >34 kg/m2), renal insufficiency (serum creatinine >1.5 mg/dL), current tobacco or illicit drug use, or alcohol intake >12 ounces per week were excluded. Subjects with abnormal values of serum electrolytes, fasting glucose, thyroid or liver function tests, or electrocardiographic evidence of heart block, ischemia, or previous coronary events were excluded. Subjects were between 18 and 65 years of age; race was self-defined. To minimize interference with assessment of the RAAS, subjects taking an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or mineralocorticoid receptor antagonist were transitioned to a dihydropyridine calcium channel blocker (amlodipine) 3 months before the study. If needed, a thiazide diuretic (hydrochlorothiazide) was added to control blood pressure. All of the antihypertensive medications were discontinued 3 weeks before study.

Subjects completed a 2-week crossover study consisting of 7 days of low-sodium intake (10 mmol per day) and 7 days of high-sodium intake (200 mmol per day). Each diet was isocaloric, contained 100 mmol per day of potassium, 20 mmol per day of calcium, and was caffeine and alcohol free. On the final day of each diet, subjects were admitted to the general clinical research center of their respective site and remained fasting and supine overnight. Sodium balance was confirmed by measurement of sodium and creatinine excretion in a 24-hour urine collection (≥150 mmol for high sodium and ≤30 mmol for low sodium). All of the hemodynamic and laboratory assessments were made in the morning. Blood pressure was measured at 5-minute intervals using an automated device (DINAMAP, Critikon); 3 consecutive readings were averaged for analysis. Protocols were standardized, and all of the assays (plasma aldosterone [ALDO], serum potassium, and plasma renin) were performed at a central laboratory as described previously.32,33 The homeostasis model assessment (HOMA) of insulin resistance was calculated as: [fasting plasma glucose (mmol/L)·fasting plasma insulin (mIU/L)]/22.5. Creatinine clearance, as determined by 24-hour urine collection, was calculated as: [urine creatinine (mg/dL)/serum creatinine (mg/dL)]x[urine volume (mL)/time (hour)x60].

Intermediate Phenotyping
Hypertensive subjects were classified according to the following intermediate phenotypes based on manipulation of the RAAS during low-sodium balance as described previously34: LR (plasma renin activity <2.4 ng/dL after 2 hours of upright posture) and normal renin. The normal-renin group was subdivided into nonmodulators (plasma ALDO response ≤15 ng/dL above baseline to infused angiotensin II [Ang II; 3 ng/kg per minute for 55 minutes]) and modulators (all others not included in the previous 2 groups).

Genotyping
Primer sequences for the 46G>A and 79C>G SNPs (rs1042713 and rs1042714, respectively) were obtained from dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). Two other nonsynonymous ß2AR polymorphisms, 100G>A (Val34Met) and 491C>T (Ile164Thr), were not included because of their rarity (minor allele frequency <5%). Genomic DNA was extracted from stored peripheral leukocytes using standard procedures. Genotyping was performed using the MassARRAY MALDI-TOF mass spectrometry platform (Sequenom).35 Duplicate genotyping was performed at each SNP in 10% of randomly selected samples. Genotype completion rates for 46G>A and 79C>G were 93% and 95%, respectively, and concordance rates exceeded 99% for each SNP.

Statistical Analysis
Statistical analysis was performed using SAS version 8.2 (SAS Institute). Hardy–Weinberg equilibrium was assessed for each SNP using {chi}2 tests. Pairwise linkage (D' and r2) was estimated by LDPlotter, and haplotypes were imputed by PHASE (Innate Immunity in Heart, Lung and Blood Disease, http://innateimmunity.net). Subject characteristics were compared by blood pressure status and by genotype. Categorical data are reported as frequencies, and continuous data are reported as the mean±SD, unless otherwise specified. Comparisons of frequencies were performed using Fisher’s exact test. All of the other analyses were performed using mixed-effect linear regression (PROC MIXED) to account for nonindependence of related subjects and were adjusted for age, gender, and study site. All of the variables were normally distributed, except plasma ALDO, plasma renin, and homeostasis model assessment, which were each natural-log transformed to achieve normality. Point estimates represent least-squares means, and error bars represent 95% CIs, both from regression. Statistical testing was based on the F-value from regression. Significance is indicated for P<0.05; all of the P values are 2-sided.

Rat Adrenal Cell Experiments
Zona glomerulosa cells were obtained from freshly isolated female rat adrenals, as described previously by our laboratory.36 All of the experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee at Harvard University. Briefly, for each cell preparation, adrenals obtained from 30 female Wistar rats (200 g) were dissected and bisected, and the capsular (glomerulosa) portion was separated from the decapsulated (fasciculata-reticularis) portion. The glomerulosa cell suspension is prepared by incubating the capsules at 37°C for 50 minutes in 15 mL of Krebs–Ringer bicarbonate buffer containing 2 mg/mL of glucose, 4% bovine serum albumin, and 3.7 mmol/L of K+ (KRBGA), supplemented with collagenase (3.7 mg/mL) and DNAse (0.05 mg/mL). The cells are centrifuged at 4°C for 10 minutes, the supernatant discarded, and the pellet washed twice and resuspended in KRBGA. This technique yields a reasonably pure cell preparation with a 6% to 9% contamination with fasciculata-reticularis cells. For each experiment, 1 to 2x105 cells/0.5 mL of KRBGA were incubated alone (basal) or in the presence of agonist (isoproterenol [10–7 M] or Ang II [10–8 M]) for 1 hour at 37°C under a 5% CO2–95% O2 atmosphere. Samples were incubated in duplicate, in the presence or absence of the ß2AR-specific antagonist ICI-118 551 (10–5 M). At the end of the incubation, ALDO release was determined in duplicate with the radioimmunoassay kit Coat-A-Count (Diagnostic Products Corporation). Data were normalized to the number of cells in each incubate and then reported as fold increase over basal level ALDO release (mean±SD).


*    Results
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 up arrowMethods
 *Results
down arrowDiscussion
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Association of ß2AR Polymorphisms and Hypertension
Subjects’ characteristics by blood pressure status are presented in Table 1. The significant differences were as expected: the normotensive subjects had lower blood pressures, were somewhat younger, and had lower body mass index and fasting glucose levels. The genotype frequency distributions in 280 hypertensive and 65 normotensive subjects were in Hardy–Weinberg equilibrium (Table 2), and the 46G>A and 79C>G SNPs were in strong linkage disequilibrium (D'=1; r2=0.40; P<0.001), both in accordance with previous studies.37,38 Three of the 4 possible haplotypes (46A/79C, 46G/79C, and 46G/79G) and only 6 haplotype combinations (diplotypes) were observed (Table 3), in agreement with previous reports.38 Variation at the ß2AR was not associated with hypertension as a phenotype (46G>A P=0.93; 79C>G P=0.92; diplotype P=0.97; Table 4).


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  		TABLE 1. Subject Characteristics by Blood Pressure Status


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  		TABLE 2. Genotype and Allele Frequencies by Blood Pressure Status


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  		TABLE 3. ß2AR Diplotypes


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  		TABLE 4. Statistical Comparison of Genotype and Diplotype Frequencies by Blood Pressure Status

Association of ß2AR Polymorphisms and Intermediate Phenotypes of Hypertension
Of the 345 total subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on both high-and low-sodium balance. Hardy–Weinberg equilibrium was confirmed in this subset (46G>A, P=0.44 and 0.99, and 79C>G, P=0.34 and 0.32, for hypertensive and normotensive subjects, respectively), and variation at the ß2AR was again not associated with the phenotype of hypertension (46G>A P=0.90; 79C>G P=0.72; diplotype P=0.85; Table 4).

To assess the relationship between each SNP and blood pressure response to dietary sodium, we compared the change (from low- to high-sodium balance) in mean arterial pressure ({Delta}MAP) by genotype and diplotype among the 171 hypertensive subjects. Although baseline (low-sodium) blood pressure was similar among genotype groups (Table 5), {Delta}MAP differed significantly by genotype (Figure 1). The 46AA and 79CC homozygotes demonstrated the greatest {Delta}MAP (mean [95% CI] in mm Hg: 16.5 [13.2 to 19.8] and 13.6 [11.3 to 15.9], respectively). Similarly, {Delta}MAP also differed significantly by diplotype (Figure 2). Consistent with the individual SNP results, the 46AA/79CC diplotype was associated with a greater {Delta}MAP compared with all of the other diplotypes combined (mean [95% CI] in mm Hg: 16.5 [13.3 to 19.8] versus 10.4 [9.0 to 11.0]; P=0.001).


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  		TABLE 5. Subject Characteristics by Genotype


Figure 1
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  		Figure 1. {Delta}MAP significantly differed by genotype at each of the 2 ß2AR loci. {Delta}MAP was assessed by the mean difference in supine systolic blood pressures obtained during high-salt and low-salt metabolic balance. Point estimates (least-square means), error bars (95% CI), and P values (F-test, 2 sided) were obtained from mixed model regression.


Figure 2
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  		Figure 2. A, {Delta}MAP differed significantly by the ß2AR diplotype. Point estimates (least-square means), error bars (95% CI), and P values (F-test, 2 sided) were obtained from mixed model regression. B, {Delta}MAP differed significantly when the 46AA/79CC diplotype was compared with all of the other diplotypes combined. Point estimates (least-square means), error bars (95% CI), and P values (F-test, 2 sided) were obtained from mixed model regression.

Two salt-sensitive intermediate hypertensive phenotypes, LR and nonmodulating hypertension, account for 50% to 60% of the hypertensive population.29 We tested whether the 46AA/79CC diplotype was associated with either of these intermediate phenotypes. We observed that the 46AA/79CC diplotype was associated with an increased frequency of LR hypertension compared with all of the other diplotypes combined (odds ratio: 3.9; 95% CI: 1.6 to 9.5; P=0.004; Table 6). No association was seen with nonmodulating hypertension (P=0.45).


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  		TABLE 6. Distribution of 46AA/79CC Diplotype in Subjects With LR and Normal-Renin Hypertension

Mechanism Underlying Hypertension in the ß2AR Variant/LR Intermediate Phenotype
LR salt-sensitive hypertension has been associated with states of relative ALDO excess.39 We, therefore, examined the relationship between plasma ALDO levels and ß2AR diplotypes. Plasma ALDO levels were measured during high-sodium balance to minimize interference from external stimulation of the RAAS. We observed that the 46AA/79CC diplotype, when compared with all of the other diplotypes combined, was associated with a significantly greater high-sodium plasma ALDO concentration (P=0.04; Figure 3). No significant association with plasma ALDO was seen when subjects were on a low-sodium diet (P=0.66). To directly assess the activity of the ß2AR on ALDO secretion, we used an isolated, partially purified glomerulosa cell model, extensively characterized by us previously.36 Our in vitro glomerulosa cell studies support the in vivo findings. The ß2AR agonist isoproterenol significantly increased ALDO secretion, whereas the antagonist ICI-118 551 reduced ALDO to baseline levels (Figure 4A). ICI-118 551 also significantly reduced Ang II-stimulated ALDO secretion (Figure 4B).


Figure 3
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  		Figure 3. High-sodium plasma ALDO, renin, and serum potassium for the 46AA/79CC diplotype versus all of the other diplotypes combined. Plasma ALDO, renin, and serum potassium were assessed as described in the Methods section. ALDO levels were significantly higher in the 46AA/79CC diplotype group, as compared with all of the other diplotypes combined (mean [95% CI]: 6.26 [4.96 to 7.90] versus 4.84 [4.35 to 5.38] ng/dL). Plasma renin and serum potassium levels were significantly lower in the 46AA/79CC diplotype group, as compared with all of the other diplotypes combined (mean [95% CI]: 106.2 [88.76 to 127.09] versus 130.4 [119.7 to 142.0] mU/L [renin]; 3.98 [3.75 to 4.20] versus 4.28 [4.15 to 4.41] mEq/L [potassium]). Point estimates (least-square means), error bars (95% CI), and P values (F-test, 2 sided) were obtained from mixed model regression.


Figure 4
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  		Figure 4. Aldosterone release from rat zona glomerulosa cells. A, Cells were either unstimulated (basal) or stimulated with 10–7 M and 10–6 M isoproterenol (ISO), in the presence (Figure 4) or absence ({square}) of the ß2AR-specific antagonist ICI-118 551 (10–5 M). B, Cells were either unstimulated (basal) or stimulated with 10–8 M and 10–7 M Ang II in the presence (Figure 4) or absence ({square}) of the ß2AR-specific antagonist ICI-118 551 (10–5 M). Aldosterone release data are shown as fold increase over basal level. Data are presented as average±SD. *P<0.05 vs basal levels; #P<0.05 vs control.

We then explored the physiological consequences of increased plasma ALDO by assessing the effect of the ß2AR diplotype on plasma renin and serum potassium, also measured during high-sodium balance. Plasma renin was used instead of plasma renin activity because of its greater range on high-sodium balance.40 We observed that the 46AA/79CC diplotype, when compared with all of the other diplotypes combined, was associated with the anticipated physiological consequences of an elevated plasma ALDO concentration, namely, lower plasma renin (P=0.03) and serum potassium values (P=0.006; Figure 3). Finally, because the {alpha}-adducin gene polymorphisms has been associated with LR hypertension,28 we assessed the distribution of these polymorphisms in our 46AA/79CC diplotype. The distribution pattern was random (data not shown).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The purpose of this study was to ascertain whether using intermediate phenotypes and diplotypes will clarify the present conflicting data concerning the role of ß2AR variants in the pathogenesis of hypertension. Previous studies have yielded conflicting results when analyzing the relationship between hypertension and variation at the ß2AR, when the phenotype has been hypertension.10–24 In our cohort with a relatively small number of normotensives subjects, we also failed to find an association with hypertension per se but were able to detect an association with intermediate phenotypes. We observed that the 46AA/79CC diplotype was significantly associated with higher blood pressure response to dietary sodium and an increased frequency of LR hypertension, with the likely mechanism being reduced suppression of ALDO secretion on a high-average sodium diet.

Salt-sensitive hypertension, characterized by an inability to excrete a sodium load without experiencing a concurrent increase in arterial blood pressure,41,42 is a common hypertensive trait, affecting {approx}60% of the essential hypertensive population. Previous studies have suggested that the ß2AR may contribute to the pathogenesis of salt-sensitive hypertension, although the mechanism has been unclear. Salt-sensitive subjects have been found to express lower fibroblast ß2AR density compared with salt-resistant individuals,43 and the decreased venodilator responsiveness to isoproterenol seen in some hypertensives has been shown to be reversed by a low-sodium diet.44 The present study demonstrates that in our cohort of hypertensive white subjects, the ß2AR 46AA/79CC diplotype is associated with a significantly higher {Delta}MAP compared with all of the other diplotypes. This finding is consistent with the previously suggested linkage between the ß2AR locus and salt sensitivity in blacks.30 In our study population, there was an insufficient number of black subjects to be analyzed separately; however, the combined results from these 2 studies suggest that the association between the ß2AR locus and salt sensitivity may be independent of ethnicity.

Data from our laboratory and others suggest that salt-sensitive hypertension can be further subdivided into 2 approximately equal, more homogeneous, groups both of which are heritable.45,46 LR hypertension is defined by an impaired renin response to RAAS stimulation (low-sodium balance, upright posture, or both),47 and nonmodulation is characterized by reduced adrenal and renal vascular responses to infused Ang II.29 Furthermore, nonmodulation, but not LR hypertension, is associated with polymorphic variants of the angiotensinogen, angiotensin-converting enzyme, and ALDO synthase genes.29 In the current study, we found no association between the ß2AR locus and nonmodulation.

Our group and others have determined previously that homozygous expression of the 460Trp allele in the {alpha}-adducin gene was significantly associated with LR hypertension, altered cellular sodium homeostasis, and impaired renal sodium handling.28,48 However, this genotype was observed in only 9% of our LR hypertensive subjects, suggesting that other factors must contribute to the LR phenotype. In the present study, we have identified another potential genetic determinant of LR hypertension, namely the ß2AR 46AA/79CC diplotype. This diplotype is associated with {approx}32% of the LR hypertensive subjects in our cohort. Although defects in ß2AR expression and functionality have been associated with LR hypertension in a few studies,49,50 to our knowledge, no previous data exist concerning the involvement of ß2AR genetic variability in the determination of this intermediate phenotype. As is true for genetic analyses of all complex traits, such as LR hypertension, it is possible that other genes, in addition to the ß2AR, contribute to the intermediate phenotype that we define as the ß2AR LR phenotype. However, we know from this study that the distribution of the {alpha}-adducin gene polymorphism described previously28 is not different other than by chance in the ß2AR subgroup. Furthermore, we have documented previously that polymorphisms in the angiotensinogen and angiotensin-converting enzyme genes are randomly distributed in the LR hypertension subgroup.29,51 Yet, conclusions of genotype/phenotype relationships need to be expressed with caution.

The level of plasma ALDO may provide a key insight into the potential mechanism for the association of ß2AR gene variation with salt-sensitive, LR hypertension. More specifically, if the excess sodium retention were secondary to factors not related to ALDO, plasma ALDO levels would be suppressed as a consequence of renin suppression. In contrast, if dysregulated ALDO secretion were contributing to the excess sodium retention, plasma ALDO levels would be elevated, with renin suppressed by physiological feedback.

Data presented herein document a relative increase in plasma ALDO levels among individuals carrying the 46AA/79CC diplotype, despite measurement during high-sodium balance, a potent suppressor of the RAAS. This finding suggests that variation at the ß2AR may modify the regulation of ALDO secretion. Further substantiating this hypothesis, the 2 physiological consequences of an increased plasma ALDO level were observed, namely, suppressed plasma renin and lower serum potassium values. We further tested this hypothesis by incubating isolated glomerulosa cells with a ß2-agonist or Ang II with and without a ß2-antagonist. ALDO release was stimulated by both isoproterenol and Ang II and reduced by the ß2-antagonist.

Our data are consistent with the previously documented association, in some subjects, between LR salt-sensitive hypertension and states of relative ALDO excess.39 Data from our group and others suggest that some LR essential hypertensive subjects display an altered adrenal sensitivity to Ang II, in terms of ALDO secretion.45,52 It is well established that the primary regulators of ALDO secretion are Ang II and serum potassium, with corticotropin influencing short-term regulation. However, a number of other factors, including adrenergic nervous system activity, have been reported to effect ALDO secretion. For example, ß2AR expression in the adrenal cortex has been documented53 and, as reported herein, ß2 agonists have been reported to directly affect ALDO production from adrenocortical cells.53–55 Cell culture experiments suggest that catecholamines may alter ALDO secretion by modulating the effect of a major stimulus, such as Ang II56; however, it is uncertain whether these results are applicable in vivo.

Given these data, how could variants in the ß2AR gene modify ALDO secretion? There are no studies directly relevant to this question. However, the 2 common variants studied herein, 46G>A and 79C>G, have been implicated previously in altered downregulation and desensitization patterns.6–8 In transfected fibroblasts, as well as in human airway cells, the 46AA/79CC diplotype display attenuated downregulation after agonist exposure compared with other diplotypic combinations.6,7 Extrapolating these findings to the adrenal gland, attenuated receptor downregulation may increase receptor availability resulting in greater ß2 agonist–mediated ALDO production or may sensitize the adrenal to endogenous stimuli for ALDO secretion, such as Ang II and serum potassium.

Interestingly, individuals treated with ß2-specific agonists frequently exhibit hypertension and hypokalemia.57,58 The observed rise in blood pressure is thought to be because of vascular ß2 and/or cardiac ß1 receptor–mediated actions, whereas the fall in serum potassium has been attributed to cellular influx related to changes in glucose and insulin metabolism.59 Our work, however, suggests a potential alternate and/or additional effect related to ALDO. Although this mechanism would not account for the rapid fall in serum potassium often clinically observed with ß2 agonist therapy, it may explain the longer-term changes seen in some experimental models.60

The sample size of our cohort may limit our statistical power to detect weak associations. For example, although we did not detect an association between genotype and hypertension, per se, our ability to detect such an association may have been limited by the relatively small number of normotensive subjects in our cohort. This limitation notwithstanding, our observation of a significant association between genotype and intermediate phenotype of hypertension provides support for using an environmentally controlled, intermediate phenotype approach to detect risk genes in complex disorders, such as hypertension. We also recognize that our analysis is limited to only 2 of the SNPs in the ß2AR gene. However, previous studies have shown that the 3 common white haplotypes detected herein capture essentially all of the underlying genetic variation.37,38

Because our study protocol necessitates that subjects withdraw all antihypertensive medications 3 weeks before study, individuals with severe hypertension were excluded. Our findings may, therefore, not be generalizable to those with more severe forms of hypertension, although such individuals comprise a minority of the hypertensive population. Although we limited our analysis to whites and adjusted for study site, subjects were recruited from 3 different countries and, therefore, residual underlying population stratification may exist. In addition, because our study only examined whites, further investigation is needed to determine whether our findings are applicable to other races, more specifically, blacks in whom a high prevalence of salt-sensitive hypertension has been documented. In support of this possibility is the report from Svetkey et al,30 which suggests that our findings may also apply to blacks. Although a few previous studies have suggested that ß2AR variation may contribute to blunted renin release in LR hypertensive subjects, our study found that the primary effect of ß2AR variation seems to be related to ALDO secretion. Our findings require replication, and further work is needed to elucidate the mechanisms by which ß2AR variation may affect ALDO secretion in humans. The strengths of this study are its careful control of experimental conditions and intermediate phenotyping.

Perspectives
We have documented that the ß2AR 46AA/79CC diplotype is associated with a greater blood pressure response to dietary sodium and a higher odds of LR hypertension, identifying 32% of the LR hypertensive subjects in our cohort. The mechanism seems to be inadequate suppression of ALDO secretion with salt intake, thereby implicating a role for the ß2AR in regulation of ALDO secretion. In conjunction with our previous work identifying an association between genetic variants of the {alpha}-adducin gene and LR hypertension, we have now identified genetic underpinnings for ≤40% of the LR population. Prospective studies are warranted to establish whether the polymorphism profile of a given individual can help clinicians treat hypertension with greater specificity.


*    Acknowledgments
 
We gratefully acknowledge the support of the dietary, nursing, administrative, and laboratory staff of the general clinical research centers in which these studies were performed.

Sources of Funding

This research was supported by the following grants from the National Institutes of Health (NIH): HL47651, HL59424, DK63214, HL069208, and a Specialized Center of Research (SCOR) in Molecular Genetics of Hypertension (P50HL055000). L.P., N.S.K., J.S.W., and T.S.P. Drs were supported in part by a training grant from the National Heart, Lung, and Blood Institute, NIH (T32HL007609). Three of general clinical research centers in which the studies were performed were supported by grants from the National Center for Research Resources, NIH (M01RR02635, M01RR00095, and M01RR00064).

Disclosures

None.


*    Footnotes
 
The first 2 authors contributed equally to the study.

Received June 14, 2006; first decision July 5, 2006; accepted August 28, 2006.


*    References
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