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(Hypertension. 1999;34:631-637.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Genetic Variants in the Epithelial Sodium Channel in Relation to Aldosterone and Potassium Excretion and Risk for Hypertension
From the Department of Medicine, Indiana University School of Medicine (W.T.A., L.J.B., L.Z., J.F.R., M.A.W., C.G., J.H.P.), and the VA Medical Center (M.A.W., C.G., J.H.P.), Indianapolis, Ind; and the Department of Internal Medicine, University of Iowa College of Medicine (P.M.S.), Iowa City, Iowa.
Correspondence to J. Howard Pratt, MD, 541 Clinical Dr, Indianapolis, IN 46202-5111. E-mail johpratt{at}iupui.edu
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Abstract |
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Abstract—Renin and aldosterone secretion is often lower in blacks than in whites, characteristics that resemble a milder form of Liddle syndrome in which a mutation in the amiloride-sensitive epithelial sodium channel (ENaC) of the kidney results in enhanced resorption of sodium. In the present study, we looked for evidence that the intrinsic level of ENaC activity is indeed higher in blacks than in whites. In overnight urine samples collected from young people (249 white and 181 black subjects, mean age 13.4 years), the urinary aldosterone/potassium ratio, which is typically very low in Liddle syndrome, was lower in blacks than in whites: 0.421±0.024 (mean±SE) versus 0.582±0.016 nmol/mmol (P<0.0001). In addition, all but 1 of 5 molecular variants in ENaC were much more common in blacks than in whites. G442V in the ß-subunit, present in 16% of the blacks and in only 1 white, was associated with parameters reflective of a greater Na retention and potentially a higher ENaC activity: a lower plasma aldosterone concentration (P=0.070), a lower urinary aldosterone excretion rate (P=0.052), a higher potassium excretion rate (P=0.048), and a lower urinary aldosterone/potassium ratio (P=0.027). In a second cohort consisting of 126 black and 161 white normotensive subjects and 232 black and 188 white hypertensive subjects, ßG442V did not show a significant association with hypertension (P=0.089). On the other hand, a variant that was twice as common in whites,
T663A, was associated with being normotensive
both in blacks (P=0.018) and in whites
(P=0.034). Expression of either ßG442V or T663A in
Xenopus oocytes did not result in a change in basal Na
current, consistent with the variants being in linkage
disequilibrium with alleles at active loci. In conclusion, several
lines of evidence are presented to suggest that ENaC activity
is higher in blacks than in whites, which could contribute to racial
differences in Na retention and the risk for hypertension.
Key Words: sodium channels • aldosterone • potassium • hypertension, sodium-dependent • race
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Introduction |
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In today's world, dietary intake of sodium is high, and although the kidney excretes most of this Na, some is retained through reabsorption. Blacks appear to reabsorb more Na than whites, as evidenced by a lower level of plasma renin activity (PRA)1 2 3 4 and greater salt sensitivity of blood pressure.5 6 7 We showed in a cohort of children that blacks also produce less aldosterone,8 9 consistent with a primary renal mechanism for increased Na retention that secondarily suppresses the renin-aldosterone axis. In addition, blacks have a greater predilection to develop hypertension than whites,10 11 which could be related to the increased Na reabsorption. Why blacks more than whites appear to retain additional Na is unknown.
The amiloride-sensitive epithelial Na channel (ENaC) in the collecting
duct of the kidney is the last site for Na reabsorption and one of the
most important.12 13 Multiple factors affect its
regulation, including aldosterone, which increases its
activity.14 15 The channel consists of 3 partially
homologous subunits: , ß, and 
.16 Mutations in
either ß- or -ENaC can result in Liddle syndrome, in which
constitutive reabsorption of Na leads to hypertension that is often
severe, hypokalemia, and suppression of renin and
aldosterone secretion.17 18 19 20 21 22 Blacks show
milder but similar features to those in Liddle syndrome, and thus there
is interest in ENaC as a contributor to the increased Na reabsorption
in blacks. Several molecular variants in ENaC have been described that
occur more frequently in blacks than in whites23 24 25 ; 1
showed an association with hypertension.24 Recently,
genetic linkage of ß- and -ENaC to systolic blood pressure
was described in white subjects.26
In the present study, we sought to identify associations between variations in ENaC subunits with parameters reflective of Na reabsorption using a study cohort of school-aged young people.27 We measured levels of renin activity and aldosterone, as well as potassium excretion and blood pressure, all of which could be affected by a more active ENaC. In a second cohort consisting of adult subjects, the association of molecular variants with the presence or absence of hypertension was studied. Subjects consisted of blacks and whites.
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Methods |
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Identification of ENaC Variants
DNA was isolated from white blood cells from groups of unrelated adults: normotensive whites, hypertensive whites, normotensive blacks, and hypertensive blacks. There were 96 subjects in each group. Sequences of
200 to 300 nucleotides were amplified by
polymerase chain reaction (PCR). Primers for the amplification reaction
in most instances hybridized to a region of intron; their sequences are
presented in Table 1. Variants were
identified by single-strand conformational polymorphism (SSCP)
analysis29 followed by dideoxy DNA sequence
analysis with the Oncor Fidelity DNA Sequencing System. Once
identified, the polymorphism was confirmed by allele-specific
oligonucleotide hybridization.
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Subjects
Normotensive Young People
The young subjects consisted of children and adolescents who
participated in a longitudinal study of blood pressure
regulation.27 None had hypertension, renal or cardiac
disease, or diabetes mellitus. The study was approved by the
Institutional Review Board of Indiana University–Purdue University of
Indianapolis. In the case of minors, informed consent was also obtained
from a parent or a legal guardian. Blood samples were obtained for
measurement of PRA and the level of aldosterone. Urine
samples were collected from bedtime to the next morning for measurement
of electrolyte and aldosterone excretion rates, with
results expressed per milligram of urinary creatinine. For
most of the subjects, urine samples were collected multiple times at
6-month intervals.
Normotensives and Hypertensives
An adult cohort was studied that consisted of individuals with
and without hypertension. Hypertensives were recruited from clinics at
the VA Hospital and Indiana University Hospital in Indianapolis.
Additional hypertensives, as well as normotensives, were recruited from
local churches and through advertisements in local newspapers. The
hypertensives were diagnosed before the age of 50 years. None had a
secondary form of hypertension as judged from clinical findings
including, when appropriate, testing of renal and adrenal function. The
majority of the hypertensive subjects were taking antihypertensive
medication at the time of recruitment. Normotensive subjects had no
history of hypertension and no known first-degree relatives with onset
of hypertension before age 50. Subjects with a body mass index (BMI)
>32 kg/m2 were excluded from the study.
All normotensive subjects had a blood pressure <140/90 mm Hg at
the time of recruitment. These studies were also approved by the
Institutional Review Board of Indiana University–Purdue University of
Indianapolis.
Genotyping
DNA was isolated from peripheral white blood cells.
In brief, genotyping consisted of amplifying appropriate genomic
fragments with PCR. DNA products were denatured with 0.4N NaOH, dot
blotted in duplicate onto Nytran (Schleicher & Schuell) membranes, and
then neutralized with 10 mmol/L Tris-Cl (pH 7.4), 1.0 mmol/L
EDTA (pH 8.0). The filters were subsequently hybridized to the
appropriate 32P-labeled
oligonucleotide in a solution containing 6X SSC, 5X
Denhardt's, 0.5% SDS, and 0.1 mg/mL denatured salmon sperm DNA for 12
hours and then washed in 2X SSC with 0.5% SDS at the appropriate
temperature for each deoxyoligonucleotide.
Blood Pressure Measurements
In the young cohort, blood pressure was measured in the right
arm with a random-zero sphygmomanometer (Hawksley and Sons) while
subjects were seated, whereas a standard mercury sphygmomanometer was
used in the adult cohort. The first and fifth Korotkoff sounds were
designated systolic and diastolic blood pressures,
respectively. Three blood pressure readings were obtained, and the
average was used for the analysis. In the case of the young
cohort, blood pressure was measured multiple times at intervals of 6
months.
Expression in Xenopus Oocytes
Two variants showed a significant association with either
parameters of Na retention or blood pressure, and
therefore, in vitro studies were performed to test for an influence of
the molecular change itself on channel function. cDNAs encoding -,
ß-, and -ENaC in expression vector pMT3 were generated as
previously described.30 31 Polymorphisms were
introduced by site-directed mutagenesis (Muta-Gene [Bio-Rad] or
Quick-change [Stratagene]), and the accuracy of the changes was
confirmed by DNA sequencing. We coexpressed -, ß-, and -ENaC in
Xenopus oocytes by nuclear injection of cDNA (0.2 ng each);
either wild-type ENaC or channels containing a polymorphism in the
(T663A) or ß (G442V) subunit were injected along with the 2
wild-type subunits. After incubation of the oocytes overnight in
modified Barth's solution, whole-cell amiloride-sensitive Na current
was determined by 2-electrode voltage clamp at -60 mV.
Amiloride-sensitive current was the current blocked by a maximal
concentration of amiloride (100 µmol/L; Sigma) added to the
bathing solution. During 2-electrode voltage-clamp recording,
oocytes were bathed in a solution containing 116 mmol/L NaCl,
2 mmol/L KCl, 0.4 mmol/L CaCl2, 1
mmol/L MgCl2, and 5 mmol/L HEPES (pH 7.4
with NaOH). Because of day-to-day variability in the experiments, we
normalized results of the experiments by dividing all measurements
within each day by that day's average current for the wild-type
channel. This resulted in the wild-type being normalized to a mean of
1.
Statistical Analysis
For normotensive young people, urinary excretion rates and blood
pressure were measured in most instances on multiple occasions, and the
number of measurements for each of the subjects was not the same (range
1 to 24 per subject). Demographic statistics for the continuous
variables were calculated by repeated-measures ANOVA, which
accounted for the varying number of measurements between people and the
within-person correlation. The compound symmetrical covariance
model was used for the final analyses. Logarithmic
transformations of the response were used for all analyses.
Included as independent variables in the repeated-measures
analysis were sex, age, and BMI, as well as genotype.
Genotype was modeled as a linear term, which assumes that the
differences in response between 0 and 1 copy of the allele is the
same as between 1 and 2 copies. In the adult cohort, the 2-sample
t test was used to compare BMI, age, and blood pressures.
The effect of genotype on the prevalence of hypertension was
tested by Fisher's exact test. Comparisons of gender frequencies also
used Fisher's exact test. For both cohorts, an exact test for
Hardy-Weinberg equilibrium was used to verify that the distributions of
the variants were in equilibrium.32 The 2-sample
t test was used to compare the in vitro Na current in
wild-type and variant groups.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Normotensive Young People
Characteristics
Table 2 depicts characteristics of the young subjects. Although similar in age to the whites, the blacks had a significantly higher mean BMI (P<0.0001). Mean systolic (P=0.038) and mean diastolic (P=0.0006) blood pressures were in each case 2 mm Hg higher in the blacks. The mean level of PRA was 19% lower in the blacks than in the whites (P=0.0041), and the means of the plasma aldosterone concentration and the aldosterone excretion rate were, respectively, 37% and 34% lower in the blacks than the whites (P<0.0001 for both values). Urinary excretion of K was 19% lower in the blacks than in the whites (P<0.0001), whereas the serum K concentration was similar in blacks and whites. The findings were consistent with observations made in previous studies of this cohort.9 33 The mean aldosterone/K ratio was significantly lower in the blacks than the whites (0.421±0.024 [mean±SE] versus 0.582±0.016 nmol/mmol; P<0.0001) (Figure 1); this was true even though the excretion rate of K in the blacks was lower than in the whites.
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Allele Frequencies
Nine nucleotide sequence variants were identified by
SSCP. Allele frequencies ranged from 3% for ßT594M to 45% for
A334T (Table 3). Three of the
nucleotide substitutions in -ENaC and 2 in ß-ENaC
resulted in an amino-acid substitution, whereas 1 in ß-ENaC and all 3
in -ENaC were silent substitutions. All variants were in
Hardy-Weinberg equilibrium with the exception of the ß-ENaC C279T
allele in the blacks, for which P=0.018 (for C279T in
whites, P=0.37). Of the molecular variants, 4 occurred
almost exclusively in the blacks (T334A and C168F in -ENaC and G442V
and T594M in ß-ENaC), whereas 1 in -ENaC (T663A) was about twice
as common in the whites. To the best of our knowledge, only
ßG442V25 and ßT594M23 24 were
described previously. No variant was found to be in linkage
disequilibrium with any of the other variants.
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Relationships of the ENaC Variants to Parameters
Reflective of ENaC Activity
Each variant was analyzed for its association with plasma
aldosterone, PRA, and urinary aldosterone and K
excretion. Only G442V in ß-ENaC showed significant associations, and
this was in the blacks, in whom the allele frequency was 0.083;
there was only 1 carrier of the allele among the whites.
Relationships to ßG442V are depicted in Table 4 and Figure 2. The magnitude of the effect is
described by the estimated slope of the regression line, which is
equivalent to the average change between individuals who have 0 or 1
copy and that between individuals with 1 or 2 copies of
ßG442V. In the presence of ßG442V, the overnight
aldosterone excretion rate was lower (P=0.052),
K excretion was higher (P=0.048), and the urinary
aldosterone/K ratio was lower (P=0.027) (Figure 2); in each case, the direction of the change was
consistent with a higher level of intrinsic ENaC activity in
the presence of ßG442V. ßG442V showed a marginal association with
the plasma aldosterone concentration (P=0.070)
but did not associate significantly with the level of PRA
(P=0.20). Because excretion rates were integrated values and
were often measured multiple times, they provided more stable values
and were thus possibly more representative of ENaC
activity than were values derived from single plasma samples. This
could explain the stronger associations with the urinary excretion
rates. All the other variants showed no significant association with
any of the parameters, and none of the variants were
significantly related to blood pressure.
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Hypertensives and Normotensives
Characteristics of Subjects
Table 5 depicts the characteristics
of normotensive and hypertensive subjects. Black hypertensives were on
average 9 years older than black normotensives, and white
hypertensives had a mean BMI that was 1.6 kg/m2
greater than white normotensives.
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Relationships to the ENaC Variants
For none of the variants was the assumption of Hardy-Weinberg
equilibrium rejected. ßG442V, which showed an association with lower
aldosterone and K excretion rates in the other cohort, was
not a significant predictor of hypertension. Although the association
was of marginal significance (P=0.089), this resulted only
from the fact that the 9 subjects homozygous for ßG442V were
hypertensive. There was no significant difference in allele
frequencies for ßG442V in normotensive (0.117) and hypertensive
(0.120) subjects (P=1.000). The T663A genotype,
which was more common in whites than blacks, showed a significant
association with being normotensive both in whites (P=0.034)
and in blacks (P=0.018). The allele frequencies for
T663A were 0.234 and 0.152 in black normotensives and hypertensives,
respectively (P=0.006), and 0.370 and 0.287 in white
normotensives and hypertensives, respectively (P=0.023).
Thus, T663A appeared to be protective against hypertension. None of
the other molecular variants showed a significant relationship to
either hypertension or being normotensive. (See Table 6.)
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Expression of ßG442V and T663A in Xenopus
Oocytes
We compared whole-cell amiloride-specific Na current in oocytes
expressing the wild-type ENaC with that of the mutated ENaC. Neither
ßG442V nor T663A had an effect on the Na current. Our results with
ßG442V were similar to those of Persu et al.25 The
average normalized current was 1.00±0.58 (mean±SD) for the ßG442V
wild type and 0.97±0.67 for the variant (P=0.81), and for
T663A, the average normalized current was 1.00±0.46 for the wild
type and 1.13±0.92 for the variant (P=0.52).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, the urinary aldosterone/K ratio, which is low in patients with Liddle syndrome,34 was lower in the blacks, consistent with greater Na retention, as might occur with a more active ENaC. The molecular variant ßG442V, which occurs almost exclusively in blacks, was significantly related to a lower aldosterone excretion rate and a lower urinary aldosterone/K ratio in a group of healthy young people. In black adults, however, ßG442V did not show a significant association with hypertension (P=0.089). A second molecular variant,
T663A, which was twice as common in whites, was associated
with being normotensive in blacks and in whites, 2 independent
population groups. T663A appeared to reduce the risk for
hypertension. Thus, several lines of evidence suggest that intrinsic
(non–aldosterone stimulated) ENaC activity may be higher
in blacks than in whites. Secretion of renin and aldosterone is often suppressed in blacks compared with whites,1 2 3 8 9 consistent with an ENaC that is functionally more active. In the present study, a reduced aldosterone excretion rate in the blacks was coupled to a K excretion rate that was greater than would have been predicted based on the normal relationship of K to aldosterone. K is a major stimulus of aldosterone secretion35 ; as dietary intake of K increases or decreases, as reflected in the urinary excretion of K, aldosterone secretion responds accordingly, and urinary excretion rates of aldosterone and K would be expected to change more or less in parallel. If, on the other hand, the channel functions at a higher level without additional aldosterone, then the ratio of excreted aldosterone to excreted K would be lower, aldosterone secretion being suppressed by the increase in reabsorbed Na and K excretion continuing relatively unabated in the collecting duct where K secretion is coupled to the reabsorbed Na. Also, aldosterone secretion would be less responsive to stimulation by K when the renin-angiotensin system was suppressed36 37 : a lower amount of aldosterone would be secreted for any given level of intake of K. Indeed, a very low urinary aldosterone/K ratio has been used to identify patients with Liddle syndrome.33 A lower ratio would also occur with overproduction of another mineralocorticoid, although in a previous study, we found that, if anything, levels of other mineralocorticoids were lower in blacks.38 A lower urinary aldosterone/K ratio could result from a decrease in 11ß-hydroxysteroid dehydrogenase, as occurs in apparent mineralocorticoid excess,39 or from variations in the regulation of ENaC by accessory factors40 such as the ubiquitin ligase Nedd4, which participates in removal of ENaC from the cell surface.41
ßG442V showed a significant association with
aldosterone and K excretion rates in the cohort consisting
of children and adolescents. Although none were hypertensive (some will
presumably become hypertensive eventually), this group provided us the
opportunity to study the relationship of genotype to
parameters representative of Na balance and
potentially to the origins of hypertension. These
parameters could not have been measured as accurately in
adults, in whom there may be confounding factors related to age, or in
hypertensives, in whom there are confounding factors related to the
hypertension itself and certainly to its treatment. This might
explain why the association of ßG442V with hypertension was not
detectable. On the other hand, T663A was associated with being
normotensive and showed no association with parameters of
Na balance in the young cohort. In the case of T663A, quite the
opposite might occur, with age being important to its
physiological expression. Our studies did not
consider potential physical interactions between variants, such as
between A334T and ßG442V, which are both quite common in
blacks.
In our search of the coding regions, no polymorphism was
found in the proline-rich sequence that is altered in Liddle
syndrome.42 With the exception of T663A, the common
molecular variants were more prevalent in the blacks than in the whites
(Figure 3), which raises the question of
whether such modifications in the channel in blacks contribute to the
efficiency of Na reabsorption and to the salt-sensitive hypertension
that is common in blacks. In a study of blacks from
London,24 although not in a study of US
blacks,23 the ßT594M variant was found to be associated
with hypertension and a lower level of PRA. In the present study,
no significant association of ßT594M with hypertension was observed,
nor were there associations with parameters of Na balance.
The estimated power for comparing the prevalence of hypertension
between carriers and noncarriers of ßT594M in our cohort was 72.6%
by a 2-sided test at the 5% level, which assumed the difference was at
least as large as in the London study, and thus we had moderate power
for detecting such a relationship.
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The allele frequency of T663A was higher in the whites,
who as a group are less likely to develop hypertension. To the extent
that T663A might be a marker of white ancestry, the presence of
T663A in blacks could simply reflect the proportion of genes of
white origin that affect blood pressure. This did not appear to be the
case, however, because the relationship of T663A to blood pressure
was significant in whites as well as in blacks.
In summary, parameters reflective of Na retention, together with significant associations of ENaC variants with either the state of Na balance or with hypertension, indicate that there may be increased ENaC activity in blacks. Different levels of intrinsic ENaC function may contribute to racial differences in Na reabsorption and the risk for hypertension.
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Acknowledgments |
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This study was supported by NIH grants R01-HL-35795 and M01-RR00750, a Merit Review grant from the US Department of Veterans Affairs, and the American Heart Association, Indiana Affiliate (L.J.B.). Studies performed at the University of Iowa College of Medicine were supported by a fellowship from the Roy J. Carver Charitable Trust (P.M.S.) and by NIH grants HL-03575, HL-58812, and DK-52617. The authors are grateful for the excellent laboratory assistance of Priya Kulkarni.
Received April 4, 1999; first decision May 28, 1999; accepted June 10, 1999.
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