(Hypertension. 1999;34:649-654.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
The Role of 
-Adducin Polymorphism in Blood Pressure and Sodium Handling Regulation May Not Be Excluded by a Negative Association Study
From Clinica Medica (N.G., F.F., C.T., A.S., F.D., P.P.P.), University of Sassari Medical School, Sassari, Italy; and the Chair of Nephrology, University of Milano, Division of Nephrology, Dialysis and Hypertension (P.M., P.S., C.B., C.L., M.T.S.A., D.C., G.B.), San Raffaele Hospital, IRCCS, Milano, Italy.
Correspondence to Nicola Glorioso, MD, Clinica Medica, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy. E-mail glorioso{at}ssmain.uniss.it
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Abstract |
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Abstract—The basic requirement for declaring an association study positive is that the "hypertension-favoring" allele is more frequent in hypertensive cases than in normotensive controls. However, both positive and negative associations with hypertension have been found for the same polymorphism when studied in different populations. In the present study, we addressed the question of the possible cause(s) of this discrepancy among populations by using the
-adducin
polymorphism as a paradigm. Four hundred ninety hypertensives and
176 normotensives enrolled in Sassari, Italy, and 468 hypertensives and
181 normotensives enrolled in Milano, Italy, were genotyped for
the -adducin Gly460Trp polymorphism. The blood pressure response
to 2 months of hydrochlorothiazide therapy could be
evaluated in 143 (85 in Sassari and 58 in Milano) hypertensives with
and without the 460Trp -adducin allele. The -adducin 460Trp
allele was not significantly more frequent in hypertensives in the
Sassari population but was more frequent in hypertensives than in
normotensives in Milano (P=0.019). Basal plasma renin
activity was lower and blood pressure fall after diuretic
therapy more pronounced (P<0.01) in hypertensives
carrying at least one 460Trp allele than in Gly460Gly homozygotes,
irrespective of their membership in the Sassari or Milano cohort. The
effect of -adducin genotype in predicting basal plasma renin
activity and blood pressure decrease with diuretic treatment is
similar in Sassari and Milano, despite the lack of association of the
-adducin genotype with hypertension in Sassari.
Key Words: genes • hypertension, genetic • sodium • renin • adducin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Population association studies have been gaining prominence to unravel the genetics of complex diseases such as hypertension. The basic requirement for declaring an association study positive is that the "hypertension-favoring" allele is more frequent in hypertensive cases than in normotensive controls. However, both positive and negative associations with hypertension have been found for the same polymorphism when studied in different populations. In the present study, we addressed the question of the possible cause(s) of this discrepancy among populations with the use of the
-adducin polymorphism as a paradigm.
The human -adducin 460Trp allele may be considered a putative
hypertension-favoring allele because it may affect blood pressure
by increasing renal tubular reabsorption through the activation of
Na,K-ATPase. Linkage and association studies, performed with markers
mapping in the region of the -adducin locus and with the Gly460Trp
-adducin polymorphism, respectively, yielded positive
results.1 Hypertensive patients carrying at least one
460Trp allele compared with those homozygous for the Gly460
wild-type allele have (1) a less-steep pressure natriuresis slope;
ie, they need a higher arterial pressure to excrete the
same amount of sodium after saline infusion2 ; (2) lower
plasma renin activity1 ; (3) enhanced proximal tubular
reabsorption3 ; and (4) a more pronounced blood pressure
fall after acute sodium depletion or chronic (2 months)
diuretic treatment.1 The 460Trp -adducin
allele displays a higher affinity for Na,K-ATPase than does the
460Gly allele.4 This last finding is of particular
relevance, because it demonstrates the same functional protein
alteration in both the rat and human "hypertensive" -adducin
variant, despite a difference in the mutation site.4 5
Therefore, these similarities in renal and protein functional
abnormalities between rats and humans justify the use of data on rats
as an argument to reinforce the concept that the 460Trp variant may be
a hypertension-favoring allele in humans.
On the other hand, our previous report of a positive association
between hypertension and the 460Trp allele has been confirmed by
some6 7 but not by others.8 9 The weaknesses
of such type of studies have been discussed in detail
recently.10 The discrepancies of results obtained in
studying different populations may be due to a number of causes,
including the interaction with other gene polymorphisms that may
counteract (or differentially modulate) the effect of the "culprit"
allele under investigation on blood pressure. For instance, so far
as -adducin is concerned, if, in a given population, another
as-yet-undetected gene variant that reduces tubular sodium reabsorption
is found more frequently in the normotensives than in hypertensives, it
may blunt the difference of the -adducin 460Trp allele frequency
between hypertensives and normotensives in this population.
This hypothesis implies the persistence of differences in the parameters reflecting the relationship between body sodium and blood pressure, such as plasma renin and blood pressure response to diuretics, between hypertensive patients homozygous for the 460Gly wild-type allele and those with at least 1 copy of the 460Trp allele. Therefore, these 2 parameters were measured in the hypertensives of 2 case-control studies differing for the presence or absence of an association between hypertension and the 460Trp allele.
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Methods |
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Association Study
The study populations consisted of 490 essential hypertensive patients and 176 normotensive controls enrolled at the Clinica Medica, Sassari University Medical School, Sassari, Italy, and 468 essential hypertensive patients and 181 normotensive controls enrolled at the Division of Nephrology, San Raffaele Hospital, Milano, Italy. All of the subjects were unrelated. The patients and controls selected in Milano are an expansion of our previously published sample.1 In particular, the number of hypertensives in the Milano sample was increased from 282 to 468 (
40% more), whereas
that of the normotensives was increased from 151 to 181 (17% more)
compared with those in the previous article.1 We decided
to increase the numbers of subjects in the Milano sample according to
those reached in Sassari, because we wanted to have 2 samples with an
equal number of cases and controls. Selection criteria for the
hypertensive and normotensive samples selected in Sassari were the same
as those of the Milano sample already published.1 Both in
Milano and Sassari, great care was taken to enroll only cases and
controls who were able to trace their origin (North Sardinia or
northern Italy) back to at least their grandparents. Although ethnic
stratification is practically impossible in Sardinia because there is
practically no migration, it may be relevant in Milano. However, we
should have been able to avoid major ethnic stratification in Milano
also, because the major migrations from the south of Italy occurred 30
to 40 years ago.
Response to Diuretic Treatment
As mentioned above, the response to 2 months' treatment, the
first with 12.5 mg/d hydrochlorothiazide PO and the
second with a double dose of the same drug, is an extension of a
previously published study.1 One hundred sixty mildly to
moderately hypertensive outpatients were studied after informed,
written consent was obtained from each participant and after approval
by the Ethics Committee of the 2 universities (95 of them selected in
Sassari and 65 in Milano). Blood pressure was measured with a
sphygmomanometer and, for each patient, all measurements were made by
the same investigators (P.S., C.T.) at the same time of day (8 to 10
AM). Ten consecutive measurements were recorded after
the patient had been clinically examined and after a 10-minute rest in
the supine position. The last 3 blood pressures were averaged and used
for the analysis. Thirty patients who had been taking
antihypertensive medications discontinued them for at least 4
months. In general the therapy withdrawal was spontaneous, and
in the majority of patients it occurred during the summer because of
the blood pressure reduction during this season. We decided to perform
such an unusually long period of therapy withdrawal because we wanted
to avoid any residual carryover effect. During this period, blood
pressure was monitored every 2 to 3 weeks. Ten patients were withdrawn
during the washout phase because of diastolic blood
pressure persistently >105 mm Hg (n=3) or <95 mm Hg (n=4)
or withdrawal of informed consent (n=3). Preliminary data from some of
these patients (26 selected in Milano and 32 in Sassari) have already
been published.1 Of that original sample, 14 were
previously treated thus only 6 more previously treated patients were
included in the present analysis.
Blood and urine samples for plasma renin activity, urinary sodium and potassium, creatinine clearance, and urinary volume were collected on the last visit before starting the treatment. Body mass index (BMI) was computed as body weight (kg)/height squared (m2). Systolic, diastolic, and mean blood pressures were used in the analysis. Mean blood pressure was computed as diastolic pressure plus one third of the pulse pressure.
Genotyping for -Adducin Polymorphism
All individuals were genotyped for the -adducin
polymorphism as previously described.1
Statistical Analysis
All clinical parameters are expressed as mean±SEM.
Blood pressure and anthropometric variables were compared with
Student's t test. Sex ratios and allele-disease
association were tested by 
2. To test for
possible false-positives of the association between the -adducin
polymorphism and hypertension, logistic regression was also
applied, entering as the dependent variable the genotype
for -adducin (contrasting Gly460Gly versus Gly460Trp+Trp460Trp),
hypertensive status and sex as categorical covariates, and age and BMI
as continuous covariates.
Blood pressure change after diuretic treatment was analyzed with multivariate ANOVA (MANOVA) for repeated measures, with 1 fixed factor within patients (blood pressure at 2 times, ie, before and after diuretic treatment) and 2 fixed factors between patients (genotype at 2 levels, Gly460Gly and Gly460Trp+Trp460Trp, and ethnicity at 2 levels, Milano and Sassari). To also take into account the effect of possible confounders originating in anthropometric differences between the hypertensives studied in Sassari and those studied in Milano, BMI, sex, and age were also entered as covariates in the model. Statistical analysis was performed with SPSS statistical software.
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Results |
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Association Study
The main clinical characteristics of the 2 hypertensive and control populations are summarized in Table 1. Owing to the study design in both populations, the controls were older than the hypertensives. BMI was larger in hypertensives than in controls as already shown and discussed.11 However, the Sassari population as a whole had a higher BMI, and the Milano population had a greater proportion of men than women.
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The frequency of the -adducin 460Trp allele was not
significantly different between hypertensives and controls in the
Sassari population (Table 2), but it
remained higher in hypertensives than in normotensives in Milano
(P=0.019), as previously reported.1 No
significant deviation from Hardy-Weinberg equilibrium was present
in hypertensives and normotensives both in Milano and Sassari (data not
shown).
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Interference of Other Clinical Variables on the Results of the
Association Study
Owing to the study design, the control subjects were older than
the hypertensives. Also, differences in BMI and sex distribution were
present between groups. Because such differences may have
contributed to contrasting findings (significant allele-disease
association in Milano versus no allele-disease association in
Sassari), we performed several analyses to test for this
possibility and were able to exclude it.11
The effect of age was tested in 2 ways. Ninety-eight hypertensive patients from Sassari and 60 from Milano were >60 years old at the time of blood sampling, but they were included in the sample because their hypertension had been diagnosed many years before (when they were <60). The frequency of the 460Trp allele in this subgroup of hypertensives was not different when compared with that of younger hypertensives in both Milano and Sassari (P=0.66 and P=0.28, respectively). However, because the sample of hypertensives >60 was indeed relatively small, the analysis was repeated by using as a cutoff the median of age of hypertensives (49 years for Milano and 50 years for Sassari). In this case also, no difference was found, indicating that there was no selective loss of the 460Trp allele with increasing age in Milano as well as in Sassari. The same kind of analysis was also repeated for BMI by using as a cutoff the median of BMI, and again none of the comparisons resulted in significant differences.
The effect of sex may have been an important confounding variable, because the number of hypertensive females was less than half the number of hypertensive males in the Milano sample, whereas sex distribution was much better balanced in the other 3 groups. However, also in this case, when tested as before, sex did not appear to play any significant role in determining the relative frequencies of the allele distribution in the subsamples.
Finally, because multiple univariate comparisons may not be
as sensitive in clarifying the role of confounders in determining
spurious allele-disease association, logistic regression was also
applied, with the genotype for -adducin as the dependent
variable, hypertensive status and sex as categorical covariates,
and age and BMI as continuous covariates. Confirming the results of the
allelic association, the presence of at least one 460Trp allele in
the genotype was also significantly associated with
hypertension only in Milano, whereas no association was found in
Sassari. None of the other variables (sex, age, and BMI) gave a
significant contribution to the model (as well as their interactions;
not shown), as summarized in Table 3.
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Response to Diuretic Treatment According to
-Adducin Genotype
Clinical characteristics of the Sassari and Milano hypertensives
are summarized in Table 4. Seven patients
did not complete the study because of hypokalemia (2 to 3.5
mmol/L, n=4) or other side effects such as epigastralgia (n=1) and
dizziness (n=2). Only the 143 patients who completed the study were
considered for statistical analysis. Because 460Trp homozygotes
are rare, the 5 homozygous patients that we found were included in the
460Trp heterozygote group. The Sassari hypertensives were older, with a
higher BMI and urinary potassium excretion than in Milano
hypertensives. The latter had a higher proportion of men than women,
but sex did not influence blood pressure response to diuretic
treatment (P=0.133).
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Basal plasma renin activity was lower in hypertensives bearing at least
one 460Trp allele than in 460Gly homozygotes, irrespective if they
were of Sassari or Milano origin (the
Figure, lower panel). Average mean blood
pressure decreased after diuretic treatment significantly more
in hypertensives bearing at least one 460Trp allele than in the
460Gly homozygotes (F=13.57, P<0.001). The overall mean
blood pressure decrease was slightly more pronounced in the Sassari
than in the Milano group (F=3.39, P=0.068), but that because
of -adducin genotype was the same in both cohorts (F=0.02,
P=0.92; the Figure, upper panel; actual data of mean
blood pressure before and after treatment are also reported in Table 4). However, when sex, BMI, and age were also entered in the
repeated-measures MANOVA model as covariates, the slightly though
nonsignificantly larger mean blood pressure decrease in Sassari than in
Milano was no longer evident (F decreased from 3.39 to 1.06, and
P increased from 0.068 to 0.306).
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Interference of Previous Antihypertensive Treatment With the
Response to Thiazide Diuretics
Despite the long pharmacological washout (4 months), one can never
exclude a carryover effect. Although we do not have any suggestion that
-adducin polymorphism played any role in the carryover, we
excluded that possibility by simply reanalyzing our sample after we
excluded those 20 previously treated patients and obtained the same
results (data not shown).
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Discussion |
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In the present case-control study, we found no association of the 460Trp
-adducin allele with hypertension in a large
population from Sassari. Conversely, we confirmed a positive
association in the enlarged population of Milano.1 In our
previous article,1 hypertensives with the 460Trp
allele displayed a lower plasma renin activity and a more
pronounced blood pressure fall with chronic diuretic treatment
compared with the patients homozygous for the 460Gly allele. These
findings are confirmed in this enlarged population of Milano and
Sassari, despite the discrepancy in the results of the association
study.
Because the sample size and the allele frequencies were similar in
the 2 populations, we may assume that a power factor was not
responsible for the discrepant results. The lack of association of the
460Trp allele with hypertension in Sassari may depend on 2 groups
of causes: (1) Because of the weak effect of the 460Trp allele on
hypertension in the overall population of patients, the detection of a
positive association may be heavily dependent on a mild case-control
difference in confounding factors, such as population stratification,
environment, lifestyle, age, BMI, and sex. Tables 1 and 4
show differences between the 2 populations in BMI, sex, and potassium
intake that may be relevant in this regard. However, as in our previous
analysis,1 11 here we excluded an influence of
BMI, age, and sex on the -adducin allele distribution. (2) A
different frequency between Sassari hypertensives and normotensives of
another gene variant, affecting either the constitutive effect of the
460Trp allele on tubular reabsorption or on the sequence of events
linking the rate of tubular reabsorption to arterial
hypertension, is also possible.
The rate of tubular reabsorption is determined by the interaction of many cellular proteins, besides other extracellular factors (physical, hemodynamic, hormonal, etc). We already know several proteins whose genetic variants may affect tubular reabsorption differently.12 It is then conceivable that the faster rate of tubular reabsorption, which may be responsible for a genetic form of hypertension, may be achieved through different molecular genetic mechanisms in different populations.
It should be recalled that in all positive association studies, the putative causal allele is indeed more frequent in hypertensives, but it is also found in a substantial number of normotensives. This is obviously due to the multifactorial nature of essential hypertension and means that, besides other mechanisms, 1 or more alleles of some other gene(s) must be present and counteracting the effect of the allele associated to hypertension in a substantial number of individuals who will eventually remain normotensive, despite the presence of the hypertensive allele.
Our hypothesis is that in Sassari (but not in Milano), more people
remain normotensive despite the presence of the 460Trp allele
because more also have the counteracting allele of 1 or more
as-yet-undetected other genes. According to the theory of evolution by
bricolage,13 it is possible to postulate that different
populations "use" the alleles available to achieve the
modulation of the peculiar cellular function needed to optimize their
biological fitness for their particular environment. Selective pressure
may favor the genetic mechanisms devoted to body sodium conservation,
either by decreasing the frequency of alleles that depress the rate
of reabsorption or by increasing the frequency of those that enhance
it. This mechanism may affect the distribution of any given allele
among cases and controls but will not affect its intrinsic specific
effect on cell functions. If the 460Trp -adducin allele
increases tubular reabsorption, then the lack of difference between
cases and controls may simply be due to some other gene variant that
counteracts the effect of the 460Trp allele on tubular
reabsorption, whose frequency could differ between Sassari
hypertensives and normotensives.
Because there is no reason to postulate that this counteracting
allele is in linkage disequilibrium with -adducin, it is most
likely inherited independently of -adducin. This implies that such
an allele is distributed evenly between the different -adducin
genotypes, allowing detection of the 460Trp allele effect
on sodium retention in hypertensives. In fact, within the hypertensive
patients of Sassari, the 460Trp -adducin allele remains
associated with lower renin and a greater blood pressure fall after
chronic diuretic treatment, implying a similar effect on renal
sodium handling of the 460Trp allele in both Milano and
Sassari.
May the -adducin 460Trp allele still be considered a
hypertension-favoring allele that increases blood pressure in the
Sassari population? The answer to this question may be either negative
or positive according to the type of study considered. It is negative
if we consider the association study but positive if we consider that
Sassari hypertensives bearing the 460Trp allele have low renin and
a larger blood pressure fall in response to diuretic
treatment.
A hypertension-favoring allele may act in 2 ways: (1) It may
produce a dysfunction in the physiological
mechanisms regulating sodium balance and blood pressure; therefore,
some abnormality of these mechanisms may also be detectable in
normotensive subjects. (2) It may hinder compensatory mechanisms that
normally counteract the development of hypertension. The example of the
progressive reduction of renal function with age may be illuminating in
this regard. At least some subtypes of essential hypertension may be
caused by the inability of the homeostatic mechanisms controlling
sodium balance to keep blood pressure low, despite the age-dependent
reduction in renal function. The alleles that cause this form of
hypertension are present from birth, but hypertension and altered
sodium balance develop only in adults, when larger-than-due sodium
retention ensues and causes low-renin hypertension. The recent
article by Kamitaniet al,14 wherein no
significant -adducin–related difference in renin/sodium
metabolism in a sample of young, normotensive individuals
could be detected (although a trend toward lower plasma renin activity
values increasing the dose of 460Trp alleles was also seen in this
sample), make the latter hypothesis more likely.
The rat studies have clearly shown an epistatic interaction between the
polymorphisms of -, ß-,15 and 
-adducin (G.B.
et al, unpublished observations, 1999) in determining the final
blood pressure level. Despite extensive studies on 20 normotensives and
20 hypertensives with single-strand conformational polymorphism
techniques (N.G. et al, unpublished observations, 1999), no
polymorphism has been detected in humans for ß- or -adducin
cDNA. Of course, these preliminary negative findings do not exclude the
possibility that a still-unknown polymorphism in these 2 genes may
be present in different populations and, because of their epistatic
interaction, that they may influence the assessment of the pressor role
of the -adducin polymorphism.
In conclusion, the major finding of the present article is that the
effect of -adducin genotype in predicting basal plasma renin
activity and blood pressure decrease with diuretic treatment is
similar in Sassari and in Milano, despite no association of -adducin
genotype with hypertension in Sassari. Our findings would
prompt the search for a difference in the distribution between
Sardinian hypertensives and normotensives of an allele of another
gene counteracting the effect of -adducin.
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Acknowledgments |
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This work was supported in part by the Ministero Università e Ricerca Scientifica of Italy (ex MPI 60%; years 1996 to 1998 to N.G., D.C., and G.B. and grant 9806154140 001 to G.B.), by Sigma Tau/MURST, National Research Project on Genetic and Molecular Analysis of Physiologic and Pathologic Response of Endocellular Receptors, and by Telethon grant No. E.C. 516.
Received April 19, 1999; first decision April 27, 1999; accepted May 26, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Cusi D, Barlassina C, Azzani T, Casari G, Citterio
L, Devoto M, Glorioso N, Lanzani C, Manunta P, Righetti M, Rivera R,
Stella P, Troffa C, Zagato L, Bianchi G. -Adducin
polymorphism in primary hypertension: linkage and association
study; relationship to salt sensitivity. Lancet. 1997;349:1353–1357.[Medline]
[Order article via Infotrieve]
-
Manunta P, Cusi D, Barlassina C, Righetti M, Lanzani
C, D'Amico M, Buzzi L, Citterio L, Stella P, Rivera R, Bianchi G.
-Adducin polymorphisms and renal sodium handling in essential
hypertensive patients. Kidney Int. 1998;53:1471–1478.[Medline]
[Order article via Infotrieve]
-
Manunta P, Burnier M, D'Amico M, Buzzi L, Maillard M,
Barlassina C, Lanella G, Cusi D, Bianchi G. Adducin polymorphism
affects renal proximal tubule reabsorption in hypertension.
Hypertension. 1999;33:694–697.
[Abstract/Free Full Text] - Ferrandi M, Slardi S, Tripodi G, Barassi P, Rivera R, Manunta P, Goldshlager R, Ferrari P, Bianchi G, Karlish SJD. Interaction between adducin and Na,K-ATPase: differential effect of hypertension related human and rat adducin polymorphisms. Am J Physiol. In press.
-
Tripodi G, Valtorta F, Torielli L, Chieregatti E,
Salardi S, Trusolino L, Menegon A, Ferrari P, Marchisio PC, Bianchi G.
Hypertension associated point-mutations in the adducin and ß
subunits affect actin cytoskeleton and ion transport. J Clin
Invest. 1996;97:2815–2822.[Medline]
[Order article via Infotrieve]
-
Castellano M, Barlassina C, Muiesan M, Beschi M,
Cinelli A, Rossi F, Rizzoni D, Cusi D, Agabiti-Rosei E.
-Adducin gene polymorphism and cardiovascular
phenotypes in a general population. J
Hypertens. 1997;15(pt 2):1707–1710.
-
Iwai N, Tamaki S, Nakamura Y, Kinoshita M.
Polymorphism of -adducin and hypertension.
Lancet.. 1997;350:369.[Medline]
[Order article via Infotrieve]
-
Kato N, Sugiyama T, Nabika T, Morita H, Kurihara H,
Yazaki Y, Yamori Y. Lack of association between the -adducin
locus and essential hypertension in the Japanese population.
Hypertension. 1998;31:730–733.
[Abstract/Free Full Text] -
Ishikawa K, Katsuya T, Sato N, Nakata Y, Takami S,
Takiuchi S, Fu Y, Higaki J, Ogihara T. No association between
-adducin 460 polymorphism and essential hypertension in a
Japanese population. Am J Hypertens. 1998;11:502–506.[Medline]
[Order article via Infotrieve]
- Schork NJ. Genetically complex cardiovascular traits: origins, problems, and potential solutions. Hypertension. 1997;29(pt 2):145–149.
-
Casari G, Barlassina C, Cusi D, Zagato L, Muirhead R,
Righetti M, Nembri P, Amar K, Gatti M, Macciardi F, Binelli G, Bianchi
G. Association of the -adducin locus with essential
hypertension. Hypertension.. 1995;25:320–326.
[Abstract/Free Full Text] - Lifton RP. Molecular genetics of human blood pressure variation. Science. 1996;272:676–680.[Abstract]
- Duboule D, Wilkins AS. The evolution of `bricolage.' Trends Genet. 1998;14:54–59.[Medline] [Order article via Infotrieve]
-
Kamitani A, Wong ZY, Fraser R, Davies DL, Connor JM,
Foy CJ, Watt GC, Harrap SB. Human -adducin gene, blood
pressure, and sodium metabolism. Hypertension. 1998;32:138–143.
[Abstract/Free Full Text] -
Bianchi G, Tripodi G, Casari G, Salardi S, Barber BR,
Garcia R, Leoni P, Torielli L, Cusi D, Ferrandi M, Pinna LA, Baralle
FE, Ferrari P. Two point mutations within the adducin gene are involved
in blood pressure variation. Proc Natl Acad Sci U S A. 1994;91:3999–4003.
[Abstract/Free Full Text]
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C. Barlassina, C. Lanzani, P. Manunta, and G. Bianchi Genetics of Essential Hypertension: From Families to Genes J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S155 - 164. [Abstract] [Full Text]
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 B. M. Psaty, N. L. Smith, S. R. Heckbert, H. L. Vos, R. N. Lemaitre, A. P. Reiner, D. S. Siscovick, J. Bis, T. Lumley, W. T. Longstreth Jr, et al. Diuretic Therapy, the {alpha}-Adducin Gene Variant, and the Risk of Myocardial Infarction or Stroke in Persons With Treated Hypertension JAMA, April 3, 2002; 287(13): 1680 - 1689. [Abstract] [Full Text] [PDF]
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N. Glorioso, F. Filigheddu, D. Cusi, C. Troffa, M. Conti, M. Natalizio, G. Argiolas, C. Barlassina, and G. Bianchi {alpha}-Adducin 460Trp Allele Is Associated With Erythrocyte Na Transport Rate in North Sardinian Primary Hypertensives Hypertension, February 1, 2002; 39(2): 357 - 362. [Abstract] [Full Text] [PDF]
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N. Glorioso, F. Filigheddu, C. Troffa, A. Soro, P. P. Parpaglia, A. Tsikoudakis, R. H. Myers, V. L.M. Herrera, and N. Ruiz-Opazo Interaction of {alpha}1-Na,K-ATPase and Na,K,2Cl-Cotransporter Genes in Human Essential Hypertension Hypertension, August 1, 2001; 38(2): 204 - 209. [Abstract] [Full Text] [PDF]
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 A. C. Morrison, P. A. Doris, A. R. Folsom, F. J. Nieto, E. Boerwinkle, and R. A. Hegele G-Protein {beta}3 Subunit and {{alpha}}-Adducin Polymorphisms and Risk of Subclinical and Clinical Stroke Editorial Comment : Candidate Genes for Stroke: If Elected, Will They Serve? Stroke, April 1, 2001; 32(4): 822 - 829. [Abstract] [Full Text] [PDF]
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C. J. Clark, E. Davies, N. H. Anderson, R. Farmer, E. C. Friel, R. Fraser, and J. M. C. Connell {{alpha}}-Adducin and Angiotensin I-Converting Enzyme Polymorphisms in Essential Hypertension Hypertension, December 1, 2000; 36(6): 990 - 994. [Abstract] [Full Text] [PDF]
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L. Zagato, R. Modica, M. Florio, L. Torielli, M.-T. Bihoreau, G. Bianchi, and G. Tripodi Genetic Mapping of Blood Pressure Quantitative Trait Loci in Milan Hypertensive Rats Hypertension, November 1, 2000; 36(5): 734 - 739. [Abstract] [Full Text] [PDF]
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 W. Siffert G protein {beta}3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy Nephrol. Dial. Transplant., September 1, 2000; 15(9): 1298 - 1306. [Abstract] [Full Text] [PDF]
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M. L. Marro, O. U. Scremin, M. C. Jordan, L. Huynh, F. Porro, K. P. Roos, S. Gajovic, F. E. Baralle, and A. F. Muro Hypertension in {beta}-Adducin-Deficient Mice Hypertension, September 1, 2000; 36(3): 449 - 453. [Abstract] [Full Text] [PDF]
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