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(Hypertension. 1997;29:918-922.)
© 1997 American Heart Association, Inc.

Articles

Preliminary Evidence of Linkage of Salt Sensitivity in Black Americans at the ß₂-Adrenergic Receptor Locus

Laura P. Svetkey; Yuan-Tsong Chen; Sean P. McKeown; Lisa Preis; ; Alexander F. Wilson

From Duke University Medical Center, Durham, NC (L.P.S., Y.-T.C., L.P.); Louisiana State University Medical Center (S.P.M.), New Orleans; and National Institutes of Health, National Center for Human Genome Research, Baltimore, Md (A.F.W.).

	Abstract

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Abstract Salt sensitivity is a heritable trait that is a hallmark of hypertension in black Americans. Genes encoding adrenergic receptors are candidate loci for the inheritance of this hypertension-related trait because of the role of these receptors in the regulation of renal sodium excretion and vascular tone. We performed this study to determine whether these loci are responsible for some of the phenotypic variation in salt sensitivity. Hypertensive black American probands were ascertained, followed by sequential ascertainment of adult sib pairs among the first-, second- and third-degree relatives of the proband. Both hypertensive and normotensive siblings were tested for salt sensitivity by an intravenous sodium-loading, lasix volume-depletion protocol. Genotyping was performed with restriction fragment length polymorphisms in genomic DNA probed with clones containing the ß₂- and _2c10-adrenergic receptor genes. A total of 109 sib pairs was evaluated. Salt sensitivity was defined as the change in blood pressure in each individual, comparing the sodium-loaded with the volume-depleted state. Systolic pressure decreased by an average of 9.0±9%, diastolic pressure by 1.5±11%, and mean arterial pressure by 5.0±9%. Neither blood pressure nor salt sensitivity was linked at the _2c10-adrenergic receptor locus. No evidence suggested that systolic salt sensitivity and baseline blood pressure were linked at the ß₂-adrenergic receptor locus. Model-independent sib pair linkage analysis suggested that diastolic blood pressure response to sodium loading/volume depletion is linked at the ß₂-adrenergic receptor locus (P<.006). Evidence for linkage was significant at the .05 level after adjustment for the number of phenotypic traits examined.

Key Words: blacks • hypertension, genetic • genetics • sodium

	Introduction

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Salt sensitivity is defined as a change in blood pressure (BP) in response to changes in salt and water homeostasis. It is taken to be a hallmark of hypertension in blacks, found in 73% with high BP.¹ Salt sensitivity may define a relatively homogeneous subgroup in whom hypertension develops through a common pathophysiological pathway. Thus, understanding the mechanisms of salt sensitivity may enhance our understanding of the pathophysiology of essential hypertension in black men and women.

Salt sensitivity, like hypertension, has a relatively high heritable component and can be treated as a qualitative or quantitative trait.^{2 3 4 5} A number of regulatory mechanisms could potentially lead to salt sensitivity, such as sodium excretion, vascular reactivity, or both. Genes that influence these phenomena can be considered to be candidate genes for salt sensitivity. Genes encoding two adrenergic receptors (ADRs) were investigated. The ß₂-ADR gene, found on chromosome 5q31-32, regulates vascular smooth muscle relaxation. The ₂-ADR genes are involved in the regulation of vascular smooth muscle contraction, sodium excretion, and renin release. The ₂-ADR gene we investigated is located on chromosome 10q24-26 (_2c10). In this study, we used model-independent sib pair methods to test for linkage of the salt sensitivity phenotype in blacks with genotype at the ß₂- and _2c10-ADR loci.

	Methods

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This protocol was approved by the Duke University Medical Center Committee for Clinical Investigations (Institutional Review Board), and all subjects signed informed consent.

Ascertainment and Eligibility
Black families were ascertained through a single proband with hypertension, followed by sequential ascertainment of all available adult siblings (with or without hypertension) among the first-, second-, and third-degree relatives of the proband. We phenotyped and genotyped all sib pairs and genotyped all available parents of the sib pairs.

Subjects were excluded from the study if they were less than 18 years of age. In addition, subjects were excluded if they had a history of malignant or accelerated hypertension, if their diastolic BP was greater than 120 mm Hg, if there was a contraindication to discontinuing BP medications, or if they had a history of furosemide allergy. Subjects were also excluded if they showed evidence of impaired renal function (ie, serum creatinine >1.5 mg/dL [133 µmol/L], urinary protein excretion >500 mg/d, or active urinary sediment). Other exclusion criteria were myocardial infarction, cerebrovascular accident, or transient ischemic attack within the previous 6 months; congestive heart failure by history, physical examination, or chest radiograph; volume depletion; severe peripheral vascular disease; or inability to give informed consent or comply with the study protocol.

To confirm that reported parent-offspring relationships were biological, we typed parents and offspring with a battery of red blood cell markers and antigens designed to detect at least 70% of mistaken parentage.^{6 7} Subjects in whom biological parentage could not be confirmed were excluded from the analysis.

Data collected included demographic characteristics, anthropometric measurements, and plasma renin activity by radioimmunoassay. Dietary intake of sodium and potassium was estimated from 24-hour urinary excretion rates.

We performed salt sensitivity phenotyping at the Duke Clinical Research Unit using the intravenous sodium-loading/furosemide volume-depletion protocol of Grim et al.⁴ BP medication was tapered and discontinued at least 2 weeks before this evaluation.

Sodium Chloride Loading
After baseline BP measurements, normal saline (0.9%) was infused via the brachial vein at a rate of 2 L over 4 hours (8 AM to noon). The total sodium intake during this 24-hour period (intravenous plus dietary) was approximately 500 mEq (11 500 mg). Dietary potassium intake was 70 mEq/d (2730 mg/d).

Volume Depletion
Starting at 8 AM on the day after sodium loading, dietary sodium intake was limited to 10 mEq (230 mg). Dietary potassium remained at 70 mEq (2730 mg/d), and subjects were allowed no more than 25 mL water/kg. Body weight, height, and skinfold thickness were used for estimation of lean body weight. Furosemide was then administered at a dose of 1 mg/kg lean body wt (maximum, 120 mg), divided into three oral doses over the day. This dose differs slightly from the original protocol of Grim et al,⁴ which used 120 mg lasix in all subjects. This modification was made for safety purposes and to normalize the diuresis so that it was equivalent to 120 mg furosemide in a 70-kg individual. Each subject was weighed before the second furosemide dose. If weight loss due to diuresis exceeded 3% of baseline (total) body weight, the third furosemide dose was reduced to avoid symptomatic hypotension.

BP Measurements
BP was measured by trained and certified personnel⁸ before the onset of saline infusion (baseline), at the end of saline infusion (sodium-loaded), and 24 hours after the first furosemide dose (volume-depleted). Each BP measurement consisted of the average of two seated measurements made with a mercury sphygmomanometer using the same arm and an appropriately sized cuff. Subjects were seated for at least 5 minutes before each BP recording. In addition, for safety purposes, BP was measured every hour throughout the saline-loading and volume-depletion procedures.

The sodium-loading procedure was terminated before completion if systolic BP exceeded 180 mm Hg, if diastolic BP exceeded 120 mm Hg, or if symptoms related to elevated BP or volume expansion developed. The volume-depletion procedure was terminated before completion if the subject developed symptomatic hypotension. If the procedure was terminated before completion, the last BP before termination was used in the salt sensitivity calculations. One individual prematurely terminated the salt sensitivity procedure.

Interpretation
Baseline BP was defined as the average of the two seated measurements taken just before the onset of sodium infusion. As previously reported by Grim et al,⁴ salt sensitivity was defined as the continuous variables representing the decrease in systolic, diastolic, and mean arterial pressures going from the sodium-loaded to the volume-depleted state. The decrease in pressure was expressed as a percentage of the sodium-loaded pressure; similar salt sensitivity results were obtained when absolute values were used. Salt sensitivity was calculated from the formula [(BP_{sodium loaded}-BP_{volume depleted})/BP_{sodium loaded}]x100. Mean arterial pressure was calculated from the formula [(2xDiastolic BP)+Systolic BP]/3.

Genetic Analysis
Genomic DNA was extracted from leukocytes in whole blood and digested with restriction enzymes that had been previously reported to reveal polymorphisms of the ß₂- and _2c10-ADR genes.^{9 10} Probes for the full-length coding sequences were provided by Dr Robert Lefkowitz (Duke University Medical Center). Restriction fragment length polymorphisms were identified by Southern blot. Genotyping methods are described elsewhere.¹¹

Statistical Analysis
We used the Haseman-Elston sib-pair test to perform linkage analysis as implemented in SIBPAL (SAGE, 1994).¹² In the Haseman-Elston test, information from both the siblings' and their parents' marker genotypes is used to estimate, with Bayesian methods, the proportion of alleles each sib pair shares identical-by-descent (IBD) at the marker locus. In the case of the candidate gene approach, the candidate gene is itself the marker locus. For quantitative traits, the squared sib pair trait difference, in this case the difference in the degree of salt sensitivity, is regressed on the estimated proportion of alleles each sib pair shares IBD at the candidate/marker locus or a locus tightly linked to it. If the candidate locus is responsible for at least some of the variation in the degree of salt sensitivity, siblings with an estimated proportion of alleles IBD that is high (ie, they are more likely to be concordant at the candidate/marker locus) should also be similar phenotypically (ie, they should have a similar degree of salt sensitivity and thus a small squared sib pair trait difference). In this case, the slope of the regression line will be negative. On the other hand, if the candidate/marker locus or a locus tightly linked to it is not involved in the variation of salt sensitivity, there will be no change in salt sensitivity with respect to the estimated proportion of alleles IBD, and the slope of the regression will be zero. The P value indicates the probability that the observed (or a greater) slope would occur if the "true" slope were zero.

In the present study, we used parental genotype data to estimate the proportion of alleles IBD when these data were available and informative. When parental genotyping was not available, we used population gene frequencies obtained from 96 unrelated black Americans who had been previously genotyped at the ß₂- and _2c10-ADR loci.²

The inclusion of covariate information may be critical in identifying genetic components, especially if the covariate has a substantial effect on the phenotype. We used Pearson product-moment correlation coefficients to test for relationships between salt sensitivity and BP-related variables such as age, body composition, and plasma renin activity. Variables significantly correlated with salt sensitivity were included in an adjusted sib-pair analysis.

	Results

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Twenty black families were enrolled in the study. Genotype and phenotype data were available for 109 sib pairs within these families. The number of sib pairs in a sibship is represented by the formula s(s-1)/2, where s is the number of siblings in the sibship. Sibships ranged in size from two (with each sibship contributing 1 sib pair) to seven (with each sibship contributing 21 sib pairs).

Baseline characteristics of participating siblings are presented in Table 1. The mean age was 37 years (range, 19 to 58), 70% of participants were female, and 33% had hypertension.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Study Subjects

Systolic, diastolic, and mean arterial BPs at baseline (ie, before saline infusion) are presented in Table 2. As noted above, our definition of salt sensitivity was the decrease in BP going from the saline-loaded state (ie, at the end of the saline infusion) to the volume-depleted state (ie, 24 hours after the first furosemide dose). Table 2 indicates that systolic pressure decreased by an average of 9.0±9%, diastolic pressure by 1.5±11%, and mean arterial pressure by 5.0±9%. Thirty-three percent of participants had at least a 10% decrease in mean arterial pressure and therefore would be classified as salt sensitive.¹

View this table: [in this window] [in a new window]   Table 2. Baseline Blood Pressure and Salt Sensitivity

There was no significant correlation between salt sensitivity and baseline BP, weight, body mass index, urinary sodium excretion, or urinary potassium excretion. The effect of the disproportionate enrollment of women in this study was presumably minimal because salt sensitivity and sex were not significantly correlated. As previously demonstrated,¹³ salt sensitivity was significantly correlated with age (r=.33, P=.0005); therefore, linkage analyses were performed with and without age adjustment. Results with and without this adjustment were essentially identical.

Table 3 shows the results of the age-adjusted sib-pair linkage analysis. There was no evidence of linkage between any trait and the _2c10-ADR locus. At the ß₂-ADR locus, there was no evidence of linkage with baseline pressure or systolic salt sensitivity. In contrast, the linkage analysis suggests that diastolic pressure response to the sodium-loading/volume-depletion maneuver was linked at the ß₂-ADR locus (P<.006). Evidence for linkage was significant at the .05 level after adjustment for the number of traits examined (ie, baseline mean arterial pressure and systolic, diastolic, and mean arterial salt sensitivity).

View this table: [in this window] [in a new window]   Table 3. Age-Adjusted Sib-Pair Linkage Analysis

	Discussion

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The development of hypertension involves the complex interaction of several environmental and genetic influences, making the search for hypertension genes difficult. This search can be facilitated by the investigation of hypertension-related phenotypes that may lead to the identification of a population that is relatively homogeneous genetically and pathophysiologically.¹⁴ One hypertension-related phenotype of interest is the degree to which BP changes in response to changes in salt and water homeostasis. This salt sensitivity phenotype is measured as a relatively acute phenomenon but is presumed to represent a sustained response to chronic sodium intake. Indeed, BP changes in response to the saline/lasix protocol predict long-term changes in BP.¹³ Many investigators hypothesize that salt sensitivity reflects an underlying genetic predisposition to hypertension, particularly among blacks, in whom salt sensitivity is particularly prevalent.¹ We investigated the genetic basis of the salt sensitivity phenotype in black sib pairs.

The heritability estimates of salt sensitivity, ie, the proportion of the phenotypic variance that can be attributed to additive genetic effects, ranges from .34 to as high as .84 in whites³ and blacks² (and C.E. Grim, personal communication), similar to the heritability of BP itself.^{15 16}

The mechanism by which salt sensitivity might lead to sustained BP elevation is unclear despite abundant data implicating salt intake in the development of hypertension. Salt sensitivity is attributed to a renal defect in sodium excretion, but salt-sensitive individuals do not continuously expand their intravascular volume. Therefore, several hypotheses have attempted to explain the connection between salt sensitivity and the hallmark of essential hypertension, increased peripheral vascular resistance. One tenable hypothesis is that salt sensitivity represents an altered responsiveness of both the kidneys and vasculature to circulating or local factors that regulate sodium excretion and vascular tone.¹⁷ Such altered responsiveness has been demonstrated in experimental¹⁸ and human^{19 20 21 22 23} salt sensitivity. The importance of the ADRs in vascular reactivity and renal sodium excretion provided the rationale for our investigation of the ß₂- and _2c10-ADRs as candidate genes. Preliminary evidence of linkage at the ß₂-ADR locus was observed.

ß₂-ADRs are implicated in hypertension and salt sensitivity in studies suggesting deficient ß-mediated vasorelaxation.²⁴ For instance, salt loading in salt-sensitive men is associated with increased vascular resistance^{25 26 27} and failure to decrease vasoconstrictor responses to angiotensin II.²² Two additional human studies suggest increased ß2-ADR sensitivity and density in blacks with hypertension²⁸ and in individuals who show a pressor response to sodium loading.²⁹ These findings may help explain the clinical observation that ß-blockers are less effective in lowering BP in blacks than in whites, but they are seemingly inconsistent with a hypothesis suggesting impaired ß-mediated vasodilation. However, in these studies, receptor density and function were evaluated in lymphocytes²⁸ and skin fibroblasts,²⁹ which may or may not reflect conditions in tissues involved in BP regulation. Although we have not evaluated receptor density, sensitivity, or function in our subjects, our observations are consistent with our previous findings of an association between genotype at this locus and the presence or absence of hypertension in unrelated blacks.¹¹ Should evidence of linkage at this locus be confirmed by subsequent human studies, the functional correlates will need further exploration.

Although our sample size is small, these data suggest that the diastolic response to sodium loading and volume depletion is linked to the ß₂-ADR locus. On average, diastolic BP changed little in response to the salt sensitivity maneuver (mean 1.5% decline), perhaps suggesting that the observed linkage is not clinically significant. However, the diastolic BP response ranged from a decrease of 24% to an increase of 20%, suggesting the possibility of heterogeneity of this response and thus the possibility of genetic heterogeneity. The lack of linkage of the systolic response may be consistent with data suggesting that systolic and diastolic BPs are under independent genetic influences.³⁰

An alternative interpretation of our data is that the ß₂-ADR locus is simply a marker for a salt sensitivity gene in that general region of chromosome 5 but does not itself play a role in the variation of salt sensitivity. A role for the ß₂-ADR locus in the expression of salt sensitivity will require replication and subsequent confirmation of linkage with additional markers in that chromosomal region. Ultimately, the identification of variants at that locus that lead to altered receptor function will be necessary to confirm (or refute) the role of the ß₂-ADR locus.

We noted no linkage of salt sensitivity at the _2c10-ADR locus. This is somewhat surprising in light of the location and function of these receptors. ₂-Receptors are located on vascular smooth muscle cells and various cell types in the kidney and are known to influence vascular tone (both systemic and renal), proximal tubular sodium reabsorption, and renin release.³¹ However, several studies have failed to demonstrate an association of the _2c10-ADR with hypertension,^{32 33} although one report demonstrates an association in blacks.³⁴ In previous work, we noted an association of _2c10 with hypertension in whites only and not in blacks.¹¹ Thus, the role of the _2c10-ADR locus in salt sensitivity and hypertension remains unclear.

We designed this study to test a specific hypothesis concerning two ADR loci, requiring a focused and narrow approach to genotyping. A broader strategy for discovering salt sensitivity and hypertension genes, currently in progress in our laboratory, involves genomic screening. In this approach, polymorphic markers spanning the entire human genome are used to identify regions of linkage between hypertension and salt sensitivity traits and markers distributed throughout the human genome. Both approaches can be used to dissect out the genetic components underlying salt sensitivity and hypertension. The current use of the candidate gene approach provides preliminary evidence of linkage of diastolic salt sensitivity at the ß₂-ADR locus.

	Acknowledgments

 
This research was supported by Grant-in-Aid No. 92012180 from the American Heart Association and by grant RO1-HL-50176 from the National Institutes of Health (NIH). Additional support was provided by M01-RR-30, National Center for Research Resources, General Clinical Research Centers Program, NIH, and the National Center for Human Genome Research. The authors gratefully acknowledge the technical assistance of Kathryn Andersen.

	Footnotes

 
Reprint requests to Laura P. Svetkey, MD, MHS, Box 3075, Duke University Medical Center, Durham, NC 27710.

Received October 4, 1996; first decision October 11, 1996; accepted October 11, 1996.

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