From the Klinik und Poliklinik für Innere Medizin II,
Universität Regensburg, Regensburg (H.S., G.A.J.R.); Institut für
Epidemiologie und Sozialmedizin, Universität Münster, Münster
(H.-W.H.); and GSF Forschungszentrum, Institut für Epidemiologie,
München-Neuherberg (H.-W.H.); and Institut für Pharmakologie,
Universitätsklinikum Essen, Essen (W.S.), Germany.
Correspondence to Dr H. Schunkert, Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany. E-mail heribert.schunkert{at}klinik.uni-regensburg.de
Potential implications of the Gß3 gene
for the development of hypertension were initially suggested by an
excess of the 825T polymorphism in hypertensive patients of
university-based referral clinics as compared with unselected control
subjects.4 These studies encouraged us to examine
the relation between the Gß3 825T
polymorphism and arterial blood pressure in a sample of
the general population. Furthermore, we speculated that enhanced
Gi protein signaling via inhibition of cAMP
generation may suppress renin formation and result, thereby, in lower
renin yet higher diastolic blood pressure levels in
subjects carrying the Gß3 825T
genotype.
Blood was drawn from nonfasting subjects who were in a supine resting
position for at least 30 minutes. Determinations of renin were carried
out in duplicate. Immunoreactive renin was measured in a 200-µL
plasma sample by means of an immunoradiometric assay kit (Nichols
Institute, Wychen, the Netherlands), following the methods proposed by
Derkx et al.6 Prorenin was activated
nonproteolytically using the renin inhibitor remikiren. The
concentration of prorenin was calculated by subtracting the results
obtained before activation of prorenin (ie, active renin) from those
obtained after activation (ie, total renin).7
Aldosterone levels were determined in 100 µL serum by
standard radioimmunoassays (Peninsula). The cross-reactivity of this
assay with 3ß,5
After DNA purification from peripheral blood using a
standard protocol, 80 ng of genomic DNA was subjected to 35 rounds of
specific amplification using 5' TGA CCC ACT TGC CAC CCG TGC 3'(sense
primer) and 5' GCA GCA GCC AGG GCT GGC 3' (antisense
primer).4 After denaturation at 94°C, DNA was
amplified using 0.5 U of Taq polymerase at 94°C for 1
minute, 61°C for 1 minute, and 72°C for 1 minute. After a final
extension for 7 minutes, polymerase chain reaction products were
digested with BseDI (Fermentas), separated on 2.5% agarose
gels, and visualized under UV illumination. The undigested product
(TT genotype) has a size of 268 bp; complete digestion (CC
genotype) results in bands of 116 and 152 bp,
respectively.4
Statistical Analysis
Prespecified subgroups5 were used to study the
relation between daily intake of antihypertensive drugs (yes versus no;
and no or 1 drug versus 2 or more drugs) and hypertension
(antihypertensive treatment or blood pressure >95 mm Hg
[diastolic] and/or 160 mm Hg [systolic]),
and the Gß3 C825T allele status was further
analyzed using logistic regression, controlling for gender,
age, and body mass index to estimate the adjusted relative risks of
antihypertensive drug therapy in the entire sample. Values measured for
plasma renin, prorenin, and aldosterone levels were
nonnormally distributed and slightly skewed to the left. Thus,
correlation analysis used logarithmically transformed values.
Because no qualitative difference was detectable when analyses
were repeated using nontransformed variables, ß coefficients are
reported for nontransformed renin and prorenin levels, and the
aldosterone to renin ratio to allow a better estimation of
the quantitative changes related to the Gß3
C825T polymorphism. Probability values are reported for each test
and statistical model, including 95% confidence intervals for the
relative risk estimates.
Because previous studies have suggested that renin levels may be weakly
related to blood pressure levels in an inverse
fashion,8 we analyzed whether this
presumed downregulation of renin levels is affected by the
Gß3 allele status. Interestingly, untreated
hypertensive subjects carrying the TT genotype
presented with markedly depressed renin levels (n=22, 11.8±1.1
mU/L) compared with untreated hypertensive subjects with the CC (n=67,
16.8±1.6; P<0.05) or CT (n=78, 15.3±1.1;
P<0.05) genotype and compared with normotensive
individuals (all genotypes: n=306, 16.7±0.6 mU/L,
P<0.05; CC: n=150, 17.6±0.9 mU/L; CT: n=131, 16.0±1.0
mU/L; TT: n=25, 14.5±1.5 mU/L).
Significant associations between the TT genotype and
diastolic blood pressure, plasma renin, and prorenin levels
(data not shown), and the aldosterone to renin ratio
persisted after adjustment for age, gender, body mass index, and
systolic blood pressure (Figure
When all individuals including those taking antihypertensive drugs were
analyzed, the T allele was significantly related to the
prevalence of hypertension and the intake of antihypertensive
combination therapy (Table 1
Given the nature of the underlying polymorphism, namely an in-frame
deletion of the Gß3 protein associated with
enhanced signaling via pertussis toxin–sensitive
Gi proteins,4 it is
tempting to speculate that this single molecular alteration may
contribute to the distinct levels of diastolic blood
pressure and biochemical findings. First, some vasoactive factors
(including norepinephrine via
Second, renin synthesis (reflected by total renin or prorenin plus
renin levels13 ) and renin release are strongly
augmented by cAMP, ie, the intracellular messenger that is under
negative control by Gi proteins. Thus, enhanced
Gi protein–related signaling is likely to
suppress plasma renin levels.
Third, despite genotype-related differences in renin and
presumably angiotensin II levels, no differences were found
with respect to aldosterone levels. It may be interesting
to note, therefore, that some stimulatory factors of
aldosterone release (eg, angiotensin II) can
act via Gi proteins in a stimulatory fashion,
enhancing phospholipase C activity, cytosolic calcium liberation, and
the expression of the aldosterone synthase
gene.14 Thus, it may be speculated that in
individuals with the TT genotype, lower angiotensin
II levels can be compensated for by enhanced postreceptor signaling.
Thereby, aldosterone levels may be inappropriately high
given the suppressed renin levels. Taken together, the contention that
the Gß3 polymorphism may contribute to
these features seems to be well supported by recent experimental
evidence. However, further studies are necessary to confirm the
present observations and to precisely elucidate the mechanisms that
may explain the associations between the Gß3
825T allele with higher diastolic blood pressure level,
lower renin level, and an elevated aldosterone to renin
ratio. Furthermore, these effects of the Gß3
polymorphism should be reassessed with regard to enzymatically
measured plasma renin activity because this method may offer enhanced
sensitivity in the lower range of renin
levels.15
The Gß3 825T allele has been
overrepresented in prespecified
groups5 characterized by arterial
hypertension or the use of antihypertensive agents. With regard to
blood pressure regulation, these findings may underscore the
pathophysiological relevance of the
polymorphism. Moreover, these data corroborate a recent
case-control study on selected individuals that initially suggested an
association of the polymorphism with
hypertension.4 Combined, these studies on 2
distinct MONICA cohorts of the Augsburg study region in Bavaria involve
more than 1000 subjects and accumulate evidence that a polymorphism
in the Gß3 subunit gene may be related to
essential hypertension in white populations.
Given the recent experience that association studies on polygenic
disorders may have discrepant results, a word of caution has to
accompany the present findings.16 In
particular, the association between the Gß3
825T allele and hypertension has to be reproduced in other
populations and investigated in individuals of different ethnic origin.
It should be noted, however, that the molecular alteration we studied
is unique in that it was initially discovered after analysis of
a cellular defect of lymphoblasts and fibroblasts of hypertensive
subjects. Subsequently, these cells have been characterized extensively
by pharmacological and biochemical methods and shown to display
alterations in intracellular signaling and
growth.1 Furthermore, detailed analyses
of Gi protein–mediated signaling has allowed
investigators to discriminate candidate genes and thereby to discover
the polymorphism in the Gß3 subunit gene
that is related to an in-frame deletion of the wild-type
protein.3 4 In turn, the discovery of the
molecular basis of the cellular phenotype made it possible to
revisit subjects with hypertension and to test the implications using
population genetic methodologies. Thus, the alterations in
transmembrane signaling caused by the polymorphism had been
established before the Gß3 825T
genotype was assessed by the present association study,
thus giving strength to the reported findings.
In summary, this study provides evidence that low renin and elevated
diastolic blood pressure levels may be related to a splice
variant of the Gß3 subunit gene that had been
shown to enhance Gi protein–related
transmembrane signaling.
Received January 23, 1998;
first decision February 26, 1998;
accepted May 21, 1998.
© 1998 American Heart Association, Inc.
Scientific Contributions
Association Between a Polymorphism in the G Protein ß3 Subunit Gene and Lower Renin and Elevated Diastolic Blood Pressure Levels
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—Gi proteins
mediate the intracellular effects of many vasoactive and proliferative
stimuli. Recently such signaling was found to be enhanced in cultured
cells of some hypertensive subjects. A polymorphism at position 825
(C
T) of the G protein ß3 subunit gene (GNB3) was strictly related
to this phenotype. The aim of the present investigation was
to test the association between this polymorphism and blood
pressure and plasma renin levels in humans. A population-based sample
(n=608) was analyzed by questionnaire and characterized for
blood pressure; plasma renin, prorenin, and aldosterone
levels; and Gß3 C825T allele status. In individuals
without antihypertensive medication (n=474; age range, 52 to 67 years),
the polymorphism was mildly associated with diastolic
blood pressure (CC: 88.6±0.3 mm Hg, n=218; versus CT:
90.1±0.7 mm Hg, n=209; versus TT: 91.8±1.7 mm Hg, n=47;
P=0.02 for trend) but not with systolic blood
pressure. Furthermore, the 825T allele was also significantly
associated with lower renin and prorenin levels, whereas the
aldosterone to renin ratio was elevated in these subjects.
Significant associations between the 825T allele and
diastolic blood pressure, plasma renin, and prorenin levels
(inverse), and the aldosterone to renin ratio persisted
after adjustment for age, gender, body mass index, and systolic
blood pressure. Finally, when the entire sample was considered and an
adjustment was made for covariates, the presence of
arterial hypertension and the use of antihypertensive
medication were both 1.8-fold higher in the TT than in the CC
genotype group (P<0.05 and
P=0.06, respectively). This observation, if replicated
in further studies, suggests a molecular mechanism that unifies a
higher diastolic blood pressure, a lower renin level, and
an elevated aldosterone to renin ratio, ie, a combination
of features frequently found in patients with arterial
hypertension.
Key Words: hypertension • G protein • genetics • genotype • medication • renin
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Most transmembrane receptors rely on heterotrimeric
GTP-binding proteins (G proteins) to activate or inhibit
intracellular signaling cascades. Specifically, a variety of vasoactive
or growth-stimulating factors communicate via G proteins in virtually
all cardiovascular tissues. Despite this pivotal role
in the transmembrane signaling network, only recently an active
participation of G proteins was considered in the pathogenesis of
hypertension.1 In particular, immortalized
lymphoblasts and fibroblasts of highly selected hypertensive subjects
were found to respond with enhanced G protein–mediated activation of
intracellular effectors after stimulation of various
receptors.2 3 These specific receptors had in
common the ability to activate pertussis
toxin–sensitive, Gi-type G
proteins.2 3 The finding that immortalized cells
of hypertensive subjects displayed enhanced G protein–mediated
signaling suggested a genetic alteration rather than a blood pressure
effect as the underlying mechanism. Subsequently, the genes coding for
the G protein subunits Gi
2,
Gi3, Gß1, and
Gß2 were screened for polymorphisms, but
were found to be without alterations in affected hypertensive
subjects.3 However, molecular analysis of
Gß3 revealed a point polymorphism C825T
that is associated with a novel splice variant and an in-frame deletion
of 41 amino acids from the wild-type protein.4
Enhanced sensitivity to agonists that stimulate intracellular signaling
via pertussis toxin–sensitive Gi proteins was
tightly associated with this splice variant and expression of
recombinant mutated Gß3 in insect cells allowed
the modified protein to be generated in
vitro.4
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The subjects of this study had participated in the WHO-MONICA
(World Health Organization–Multinational Monitoring of Trends and
Determinants in Cardiovascular Disease), Augsburg,
baseline survey of 1984/85 and its follow-up examinations in 1987/88
and 1994.5 In 1994, biochemical and
anthropometric measurements were offered to a total of 1010 men and
women, aged 52 to 67 years, of whom 646 (64%) attended. Plasma renin
measurements and determinations of the Gß3 C825T allele status
were successfully performed in 608 of these subjects. All subjects
responded to an extensive questionnaire. Body mass index was computed
as weight in kilograms divided by height in meters squared
(kg/m2 ). Resting blood pressure level was
measured in sitting subjects after at least 5 minutes of rest using a
mercury sphygmomanometer. During this single appointment, blood
pressure was read 3 times at the right arm by 2 investigators.
The mean of 3 measurements was used for this study. Hypertension was
defined as blood pressure level 
160 (systolic) and/or 95
mm Hg (diastolic) or intake of antihypertensive agents.
Antihypertensive drugs were considered to be used for treatment of
hypertension when subjects were aware of hypertension. Antihypertensive
combination therapy was considered when drugs acting via different
blood pressure–lowering mechanisms, eg, diuretics and ACE
inhibitors, were taken either as separate pills or in a
fixed combination. -tetrahydroaldosterone and
3,5ß-tetrahydroaldosterone is 4.2% and 0.3%,
respectively. All other steroids cross-react to <0.1%.
Anthropometric data of subjects were compared according to the
Gß3 C825T allele status by ANOVA for
comparison of independent samples or 
2 test
for comparison of classified values. Regression analysis was
carried out to test for trends related to genotype. Given the
confounding effects of antihypertensive therapy, patients receiving
such treatment were excluded from comparisons of
Gß3 C825T allele status with blood
pressure, renin, and prorenin levels. A further subgroup consisted of
subjects not treated for hypertension despite blood pressure levels of
>95 mm Hg (diastolic) and/or 160 mm Hg
(systolic; untreated hypertensives).
Multivariate linear regressions, controlling for
gender, age, body mass index, and systolic blood pressure level
(or diastolic blood pressure), were carried out to further
study the relation between diastolic blood pressure, renin,
and prorenin levels and Gß3 C825T allele
status. At =0.9, the present population offered a 70% chance to
detect a 25% variation in plasma renin levels related to the
Gß3 825T allele.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
In the entire cohort and the subgroups presented below,
the genotype distribution of the Gß3
alleles was in Hardy-Weinberg equilibrium. Anthropometric and
biochemical data for individuals without antihypertensive medication
are listed in Table 1
. The T allele
was found to be significantly related to higher diastolic
blood pressure and, in an opposite fashion, to renin and prorenin
levels. Because aldosterone levels were not significantly
affected by the Gß3 allele status, the
polymorphism was also related to an increased
aldosterone to renin ratio. Other parameters
(including age, gender, heart rate, body mass index, and
systolic blood pressure level) displayed no significant
differences between the CC, CT, and TT genotype groups (Table 1).
View this table:
[in a new window]
Table 1. Anthropometric and Biochemical Data in Participants
Without Antihypertensive Treatment and Hypertension Status in All
Participants ).
Furthermore, significant associations between the
Gß3 allele status and renin and the
aldosterone to renin ratio were replicated when
diastolic blood pressure was replaced by systolic
blood pressure in the multivariate model (data not
shown).
View larger version (12K):
[in a new window]
Figure 1. Bar graphs show the association between Gß3
allele status and diastolic blood pressure level, renin
level, and aldosterone to renin ratio in untreated subjects
after correction for gender, age, body mass index, and systolic
blood pressure level (mean±SEM). The relative change in
diastolic blood pressure (mm Hg), renin (mU/L), and the
ratio of aldosterone level to renin level is related to
respective genotypes, using subjects without the
polymorphism (CC genotype) as reference. 
), a finding that persisted after
adjustment for age, gender, and body mass index (Table 2).
View this table:
[in a new window]
Table 2. Adjusted Risk for Presence of Arterial Hypertension
or Antihypertensive Drug
Treatment
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In the present study, carriers of a frequent polymorphism
at position 825 of the Gß3 subunit gene were
found to have higher diastolic blood pressure levels, lower
renin levels, and a higher aldosterone to renin ratio.
Interestingly, these features are similar to some of the alterations
found in patients with low renin
hypertension.9 2-adrenoceptors, angiotensin II,
and thrombin) are known to transmit some of their effects via pertussis
toxin–sensitive Gi
proteins.10 11 12 Thus, these vasoconstrictors, if
activated, may cause enhanced vascular resistance in
individuals carrying the mutated Gß3 protein.
Alternatively, the higher diastolic blood pressure levels
in these subjects might be explained by vascular
hypertrophy.1 In particular, growth
factors of vascular smooth muscle cells, like platelet derived
growth factor, are known to activate Gi
protein–dependent pathways.3
Acknowledgments
This study was supported by the Deutsche Forschungsgemeinschaft
(DFG Schu 672/9-1, 672/10-1, Si 393/12-2, and Ho 1038/8-1), the
Bundesministerium für Bildung, Forschung und Technologie (H.S.,
H.W.H., A.D.), the Fritz Thyssen Stiftung, and the Hans und Gertie
Fischer-Stiftung (W.S.). The authors thank the 646 men and women who
participated in this MONICA survey for the third time. Furthermore, we
thank Gerlinde Siffert, Rene J.A. de Bruin, and Susanne Kürzinger
for excellent technical support.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
i2,
Gi3, Gß1, and
Gß2 are not mutated. Circ Res. 1996;79:974–983.
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