(Hypertension. 1999;33:1049-1051.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
G-Protein ß3 Subunit C825T Variant and Ambulatory Blood Pressure in Essential Hypertension
From the Department of Internal Medicine, Division of Endocrinology and Nephrology, Universitätsklinikum Benjamin Franklin, Free University of Berlin (Germany).
Correspondence to Prof Dr Arya M. Sharma, Medizinische Klinik IV, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail sharma{at}zedat.fu-berlin.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Recent studies have identified a novel polymorphism (C825T) of the gene encoding the ß3 subunit of heterotrimeric G proteins (Gß3) associated with enhanced activation of G proteins, which appears to be more common in hypertensive patients. In the present study we examine the relationship between this genetic variant and hypertension in 479 white patients with established essential hypertension recruited from the hypertension clinic of the Universitätsklinikum Benjamin Franklin in Berlin, Germany, and 1000 normotensive gender- and age-matched controls. All patients were screened for the presence of secondary hypertension and were further characterized by ambulatory blood pressure measurements performed in 295 treated and 184 untreated patients. Genotype distribution for the Gß3-C825T genotype in patients (CC=204, CT=224, TT=51) was significantly different from that in controls (CC=514, CT=412, TT=74;
2=11.5, P<0.01), and the T allele
was associated with an odds ratio of 1.5 (95% CI, 1.1 to 2.2) versus
non-T carriers for the presence of hypertension. However, in both the
whole group and the untreated subgroup, blood pressure levels between
the genotypic groups were virtually identical. Furthermore, age of
onset of hypertension and number of antihypertensive medications (in
treated patients) were similar between the genotypic groups. Thus,
while our data confirm the association between the
Gß3-C825T variant and essential hypertension, they do
not support the hypothesis that this marker is associated with more
severe blood pressure in patients with already established
hypertension.
Key Words: angiotensinogen • angiotensin-converting enzyme • hypertension, essential • genetics • blood pressure monitoring, ambulatory • hypertrophy, left ventricular
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Arterial blood pressure is a complex quantitative trait influenced by both genetic and environmental factors.1 On the basis of the finding that high blood pressure and target-organ damage tend to cluster in families, it is anticipated that genetic markers can be identified that would allow the early detection of individuals prone to the development of hypertension and its sequelae.2
A recent study has detected a novel polymorphism (C825T) in exon 10 of the gene encoding the ß3 subunit of heterotrimeric G proteins (Gß3),3 which was significantly associated with hypertension in patients recruited from Essen, Berlin, and Heidelberg, Germany. The T variant was also associated with the occurrence of a splice variant GNB-s, in which the nucleotides 498 to 620 of exon 9 are deleted, resulting in the loss of 41 amino acids and 1 tryptophan–aspartic acid (WD) repeat domain of the Gß subunit. This splice variant was found to be predominantly expressed in cells from individuals carrying the T allele, and it appears to result in significantly enhanced activation of G proteins. It was postulated that expression of Gß3-s may contribute to the development of hypertension by increasing proliferation of smooth muscle cells and possibly cardiomyocytes, thus resulting in the development of vascular and/or myocardial hypertrophy. It was also postulated that the Gß3-C825T may be associated with late-onset rather than early-onset hypertension.
In the present study we examined the relationship between the Gß3-C825T genotype, age of onset, and severity of blood pressure in patients with established essential hypertension referred to a tertiary hypertension clinic at a university medical center.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The protocol of the study was approved by the ethical committee of our hospital, and informed consent for genetic studies was obtained from all participants
Patient Selection and Clinical Investigation
Treated and untreated white patients (n=479) from our outpatient
hypertension clinic were enrolled in the study. Resting blood pressure
was measured at each presentation by a trained nurse.
Hypertension was defined as a systolic blood pressure
>140 mm Hg and/or a diastolic blood pressure
>95 mm Hg on at least 2 separate occasions. Additionally,
ambulatory blood pressure measurements (90207, SpaceLabs Medical
Inc) were performed in all patients. Patients with white-coat
hypertension, as evidenced by elevated clinic blood pressure but
24-hour average ambulatory blood pressure <135/85
mm Hg,4 were not enrolled in the study. All patients were
thoroughly examined for the presence of secondary hypertension and
target-organ damage by standard clinical, laboratory, and imaging
procedures. Age of onset was determined by history and direct contact
with the family physician at the first time the patient was ever told
by a physician that he or she was hypertensive. In treated patients,
the number of antihypertensive medications was considered a surrogate
marker for the severity of hypertension.5 Patients who had
never been treated previously or had stopped antihypertensive
medication for any reason at least 4 weeks before presenting at our
clinic were defined as untreated. Once the presence of hypertension was
established, venous blood samples were drawn for DNA extraction and
genotyping. We also recruited 1000 healthy normotensive age- and
gender-matched volunteers among blood donors and hospital staff.
Genotyping
Genomic DNA was prepared from peripheral white blood
cells by a standard column-extraction technique (Qiagen). Subsequently,
the Gß3-C825T genotype was determined by
polymerase chain reaction amplification of the relevant region followed
by restriction with BseD1 (New England Biolabs), as
described previously.6 Complete restriction of the
polymerase chain reaction product (268 bp=TT
genotype) generated bands of 116 and 152 bp (CC
genotype).
Statistical Analysis
All data are presented as mean±SD or as proportions.
Continuous variables were compared by 2-sided Student's
t test or the nonparametric Kruskal-Wallis test
for independent samples as appropriate, and categorical data were
assessed by 2 statistics. The relationships
between both genotypes and blood pressure were examined by
linear and logistic multiple regression analysis, with gender,
age, duration of hypertension, and body mass index as covariates (SPSS
PC+, 1995). In the logistic analysis, the sample population was
divided into 2 groups on the basis of blood pressure distribution,
whereby patients in the 4th quartile of the resting and ambulatory
blood pressure distribution were considered cases. P<0.05
was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Fourteen patients were excluded from analysis because of secondary hypertension. Genotype distribution for the Gß3-C825T genotype in the remaining patients (CC=204, CT=224, TT=51) was significantly different from that in controls (CC=514, CT=412, TT=74;
2=11.5,
P<0.01), and the TT genotype was
associated with an odds ratio of 1.5 (95% CI, 1.1 to 2.2) versus non-T
for the presence of hypertension. However, in both the treated and
untreated subgroups, blood pressure levels between the genotypic groups
were virtually identical (Table).
Furthermore, age of onset of hypertension and number of
antihypertensive medications (in treated patients) were similar between
the genotypic groups. Stepwise multiple regression analysis of
the relationship between the blood pressure variables (resting
blood pressure and ambulatory 24-hour blood pressure) and
genotypes in patients consistently revealed a
significant result only for the covariates gender and age. After
adjustment for gender and treatment, the Gß3
genotype did not enter the equations in either linear or
logistic regression analysis. In a univariate post
hoc explorative analysis, gender-specific differences in blood
pressure were noted in that the T allele in the male group was
associated with higher resting blood pressure (CC:
167±17/103±16; CT: 169±24/105±14; TT:
176±31/105±19 mm Hg). However, these trends were not
statistically significant (P=0.25). Furthermore, when a
dominant effect of the T allele was assumed, an analysis of
CC patients versus the combined CT/TT
group likewise failed to reveal a significant influence of
genotype on resting blood pressure (CC:
167±17/103±16 versus CT/TT:
170±25/105±15 mm Hg; P>0.1).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The recent study by Siffert et al3 reported a positive association between the T variant of the Gß3-C825T genotype with hypertension in white subjects. Our data confirm this association, but within the patient group, the Gß3 genotype was not related to age of onset, resting and 24-hour ambulatory blood pressure, or number of medications in treated patients. Thus, while our findings provide evidence that the Gß3-C825T allele confers susceptibility to the development of hypertension, they do not support the hypothesis that this genotype is an important determinant of the severity of essential hypertension or of the age of onset of the disease.
Nevertheless, in men there was a trend toward higher resting blood pressure in the TT group, which, however, failed to reach statistical significance. On the basis of the frequency of the T allele and the observed variances in resting blood pressure levels, we calculated that it would take >2000 untreated hypertensives to statistically rule out an influence of the T allele on these variables. Ambulatory blood pressure levels, a more reproducible measure of blood pressure load7 and stronger predictor of end-organ damage,8 were virtually identical between the TT and CC groups.
It is, however, important to realize that genes conferring susceptibility to hypertension must not necessarily determine the severity of hypertension, since several other genetic or nongenetic factors may influence the expression of the phenotype in genetically susceptible individuals. Furthermore, the lack of relationship between genotype and severity of hypertension in this population does not imply that the Gß3 gene is only of marginal effect. When one considers that "essential" hypertension is a multifactorial entity, a given candidate gene may well have a strong effect on blood pressure in a subset of patients, while it may lack importance in others. This line of reasoning is evident from the fact that the T allele is also present in a large proportion of the normotensive population.
As in the first report by Siffert et al,3 the presence of
the G3ß-825T allele in our study was associated with
an odds ratio of approximately 1.5 to 1.7 for the presence of
hypertension. Why the G3ß-825T variant apparently confers
an increased susceptibility to the development of hypertension is
presently not clear. It is probably important to note that this
genetic variant, which leads to the increased expression of a splice
variant of the Gß3 subunit, was identified in cell lines
derived from hypertensive individuals selected on the basis of an
increased activity of the Na-H exchanger in immortalized lymphoblasts
and cultured fibroblasts.9 10 Increased
activity of the Na-H antiporter has been found in 
50% of patients
with essential hypertension,11 but whether this
abnormality of ion transport is directly related to the pathogenesis of
hypertension in these individuals remains unclear.
In summary, our study indicates that individuals bearing the Gß3-825T allele may have an increased risk of developing hypertension, but this is not an indicator of severity in patients with established essential hypertension presenting at a tertiary hypertension center. Whether this genetic marker may prove to be of clinical importance in an unselected group of patients with essential hypertension remains to be determined.
|
Acknowledgments |
|---|
Genotyping was supported in part by the Deutsche Forschungsgemeinschaft (DFG Sh35/2–2). We would like to acknowledge Christel Harsch, Klaus Schlotter, and Brigitte Egbers for their expert technical help.
Received November 11, 1998; first decision December 2, 1998; accepted December 10, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Ward R. Familial aggregation and genetic epidemiology of blood pressure. In Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press; 1990:81–100.
-
Lander ES, Schork NJ. Genetic dissection of
complex traits. Science. 1994;265:2037–2048.
[Abstract/Free Full Text] - Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R, Sharma AM, Ritz E, Wichmann HE, Jakobs KH, Horsthemke B. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet. 1998;18:45–48.[Medline] [Order article via Infotrieve]
- Anlauf M, Baumgart I, Franz I, Gotzen R, Krönig B, Meyer-Sabellek W, Middeke M, Schrader J, Schulte KL, Weber F. Empfehlungen der Deutschen Liga zur Bekämpfung der hohen Blutdruckes e. V.: Ambulante 24-h-Blutdruckmessung. Herz Kreislauf. 1995;27:III-VI.
- Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, Corvol P. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992;71:169–180.[Medline] [Order article via Infotrieve]
-
Schmidt S, Sharma AM, Zilch O, Beige J, Walla-Friedel
M, Ganten D, Distler A, Ritz E. Association of M235T variant of the
angiotensinogen gene with familial hypertension of early
onset. Nephrol Dial Transplant. 1995;10:1145–1148.
[Abstract/Free Full Text] -
James GD, Pickering TG, Yee LS, Harshfield GA, Riva S,
Laragh JH. The reproducibility of average ambulatory, home, and clinic
pressures. Hypertension. 1988;11:545–549.
[Abstract/Free Full Text] -
Verdecchia P, Porcellati C, Schillaci G, Borgioni C,
Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A,
Santucci C, Reboldi G. Ambulatory blood pressure: an independent
predictor of prognosis in essential hypertension.
Hypertension. 1994;24:793–801.
[Abstract/Free Full Text] - Siffert W, Rosskopf D, Moritz A, Wieland T, Kaldenberg-Stasch S, Kettler N, Hartung K, Beckmann S, Jakobs KH. Enhanced G protein activation in immortalized lymphoblasts from patients with essential hypertension. J Clin Invest. 1995;96:759–766.
-
Rosskopf D, Düsing R, Siffert W. Membrane
sodium-proton exchange and primary hypertension.
Hypertension. 1993;21:607–617.
[Abstract/Free Full Text] -
Siffert W, Düsing R. Sodium-proton exchange and
primary hypertension: an update. Hypertension. 1995;26:649–655.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  M. Sartori, A. Semplicini, W. Siffert, P. Mormino, A. Mazzer, F. Pegoraro, L. Mos, M. Winnicki, and P. Palatini G-Protein {beta}3-Subunit Gene 825T Allele and Hypertension: A Longitudinal Study in Young Grade I Hypertensives Hypertension, November 1, 2003; 42(5): 909 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Ruiz-Velasco and S. R. Ikeda A splice variant of the G protein {beta}3-subunit implicated in disease states does not modulate ion channels Physiol Genomics, April 16, 2003; 13(2): 85 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sedlacek, M. Fischer, J. Erdmann, C. Hengstenberg, S. Holmer, S. Kurzinger, M. Muscholl, A. Luchner, G. A. Riegger, H.-W. Hense, et al. Relation of the G Protein {beta}3-Subunit Polymorphism With Left Ventricle Structure and Function Hypertension, August 1, 2002; 40(2): 162 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Swynghedauw Susceptibility-conferring polymorphic genotypes in cardiovascular multifactorial syndromes Eur. Heart J., February 2, 2002; 23(4): 271 - 273. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Heusch, R. Erbel, and W. Siffert Genetic determinants of coronary vasomotor tone in humans Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1465 - H1468. [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 C. Hengstenberg, H. Schunkert, B. Mayer, A. Doring, H. Lowel, H.-W. Hense, M. Fischer, G. A.J Riegger, and S. R Holmer Association between a polymorphism in the G protein {beta}3 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction Cardiovasc Res, March 1, 2001; 49(4): 820 - 827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Wuthrich, S. Cicvara, C. Booy, U. Widmer, and U. Binswanger The 825C/T polymorphism of the G-protein subunit {beta}3 does not influence blood pressure and renal function in kidney transplant recipients Nephrol. Dial. Transplant., October 1, 2000; 15(10): 1663 - 1666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. Rosskopf, S. Busch, I. Manthey, and W. Siffert G Protein {beta}3 Gene : Structure, Promoter, and Additional Polymorphisms Hypertension, July 1, 2000; 36(1): 33 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Poch, D. Gonzalez, E. Gomez-Angelats, M. Enjuto, J. C. Pare, F. Rivera, and A. de la Sierra G-Protein {beta}3 Subunit Gene Variant and Left Ventricular Hypertrophy in Essential Hypertension Hypertension, January 1, 2000; 35(1): 214 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Dong, H. Zhu, G. A. Sagnella, N. D. Carter, D. G. Cook, and F. P. Cappuccio Association Between the C825T Polymorphism of the G Protein {beta}3-Subunit Gene and Hypertension in Blacks Hypertension, December 1, 1999; 34(6): 1193 - 1196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Siffert, D. Rosskopf, R. Erbel, E. Ritz, E. Brand, S.-M. Herrmann, and L. Tiret G Protein {beta}3 Subunit 825T Allele and Hypertension • Response Hypertension, November 1, 1999; e8(5): . [Full Text]
|
|
|
|
 |
|
 W. SIFFERT, P. FORSTER, K.-H. JÖCKEL, D. A. MVERE, B. BRINKMANN, C. NABER, R. CROOKES, A. D. P. HEYNS, J. T. EPPLEN, J. FRIDEY, et al. Worldwide Ethnic Distribution of the G Protein {beta}3 Subunit 825T Allele and Its Association with Obesity in Caucasian, Chinese, and Black African Individuals J. Am. Soc. Nephrol., September 1, 1999; 10(9): 1921 - 1930. [Abstract] [Full Text]
|
|
|
|
|
|
J. BEIGE, S. ENGELI, J. RINGEL, G. OFFERMANN, A. DISTLER, and A. M. SHARMA Donor G Protein {beta}3 Subunit 825TT Genotype Is Associated with Reduced Kidney Allograft Survival J. Am. Soc. Nephrol., August 1, 1999; 10(8): 1717 - 1721. [Abstract] [Full Text]
|
|
|
|
|
|
T. Rankinen, T. Rice, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard G protein {beta}3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study Physiol Genomics, February 28, 2002; 8(2): 151 - 157. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||