| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1999;34:1193.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Association Between the C825T Polymorphism of the G Protein ß3-Subunit Gene and Hypertension in Blacks
From the Blood Pressure Unit (Y.D., H.Z., G.A.S., F.P.C.), Department of Medicine, the Medical Genetics Unit (Y.D., N.D.C.), Department of Child Health, and the Department of Public Health Sciences (D.G.C.), St George’s Hospital Medical School, London, UK.
Correspondence to Dr G.A. Sagnella (Molecular Biology) or Dr F.P. Cappuccio (Epidemiology), Blood Pressure Unit, Department of Medicine, St George’s Hospital Medical School, Cranmer Terrace, SW17 0RE London, UK. E-mail g.sagnella@sghms.ac.uk or f.cappuccio{at}sghms.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—A polymorphism (C825T) of the G protein ß3-subunit gene has been associated with low renin hypertension in whites. The aim of this study was to examine the C825T polymorphism in relation to hypertension in a population-based study of black people of African origin who have high prevalence of low renin, salt-sensitive hypertension. A total of 428 men and women, aged 40 to 59 years (270 Caribbeans and 158 West Africans), who took part in a population-based survey were studied. All were blacks and first-generation immigrants. The C825T polymorphism was detected by polymerase chain reaction followed by restriction-enzyme digestion. The prevalence of hypertension (supine blood pressures
160 systolic and/or 95 mm Hg
diastolic or on drug therapy) was 43%. The distribution of
the genotypes (CC, CT, and TT) was in Hardy-Weinberg
equilibrium with observed frequencies of 4.0% (n=17), 33.6% (n=144),
and 62.4% (n=267), respectively. Allele frequencies were 20.8%
for C and 79.2% for T. No difference was detected between Caribbeans
and West Africans. A 3-fold higher risk of hypertension was found among
the carriers of the T variant both as heterozygotes (odds ratio [OR],
3.43 [95% CI, 0.94 to 12.4]) and homozygotes (OR, 3.87 [95% CI,
1.09 to 13.8]). The estimate of effect and the blood pressure values
in the groups carrying the T variant suggested a dominant model for the
T allele. This was confirmed by a significant association between
the T allele and hypertension (OR, 3.71 [95% CI, 1.05 to 13.1]),
even when adjusted for age, sex, and body mass index (OR, 4.14 [95%
CI, 1.11 to 15.4]). The study shows, for the first time, a high
frequency of the 825T allele in black people, and it provides
evidence that the T allele may be a susceptibility factor for the
development of hypertension in blacks. Given the high frequency of the
T allele, even a 2-fold increased risk of hypertension among the
carriers of the T allele might account for 44% of the cases of
hypertension in blacks.
Key Words: hypertension, genetic • blacks • G protein • polymorphism • epidemiology
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
GTP binding proteins (G proteins) mediate the functional responses of numerous agonists.1 Hence, variations within genes coding for these proteins may be of significance in cardiovascular disease.
Polymorphism C
T at nucleotide 825 in exon 10 of the
ß3-subunit of pertussis toxin–sensitive
Gi-type protein has recently been identified. A
significantly higher frequency of the T allele has been reported in
subjects with essential hypertension compared with unselected
normotensive control subjects of European origin in 3 independent
studies2 3 4 but not in a fourth study.5
The recombinant, mutated G protein ß3-subunit, coexpressed with
G
i2 and G
5 subunits in cell lines from hypertensive patients and
in transfected insect cells, increases sensitivity to agonists that
stimulate intracellular signaling through pertussis toxin–sensitive G
proteins.2 The mechanism whereby the 825T variant may lead
to hypertension in humans remains unknown, but it may involve increased
Na+-H+ exchanger
activity.2 Increased activity of this exchanger provides
several mechanisms of potential relevance to the development of
hypertension,6 including enhancement of renal tubular
sodium reabsorption that leads to an increase in extracellular volume.
This mechanism may play an important role, given that the 825T
allele is associated with lower plasma renin activity and an
elevated aldosterone-renin ratio.7
Therefore, the possible participation of the 825T mutation may be even more relevant to hypertension in black people of African descent, because their hypertension is characterized by low plasma renin activity, which suggests a corrected state of volume expansion.2 8 9 The aim of the present study was to examine the C825T polymorphism of the G protein ß3-subunit in relation to hypertension in black people of African origin in a population-based study.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A population-based sample of 459 men and women, aged 40 to 59 years, of black African descent (Caribbeans and West Africans) was obtained from stratified random sampling of lists from general practices in South London as previously described.9 10 Participants were all first-generation immigrants. Ethnic group was recorded at the time of interview.9 All participants gave informed consent to participate in the study, which was approved by the local ethics committee. Participants attended a dedicated screening unit at St. George’s Hospital between 8 AM and 12 PM after an overnight fast. Anthropometry and blood pressure measurements were performed as previously described.9 10 11 Details of blood collections for DNA, routine serum electrolytes, plasma aldosterone, and urine collections were also as described.9 10 11 Hypertension was defined as supine systolic blood pressure
160 and/or
diastolic blood pressure 95 mm Hg or being on
antihypertensive treatment.
Genetic Analysis
Genomic DNA was isolated from whole blood using Nucleon BACC DNA
extraction kit.11 The C825T polymorphism was detected
by PCR followed by BseDI (MBI Fermentas) restriction-enzyme
digestion as described previously, with minor
modifications;2 products were separated on 2%
agarose gels and visualized under UV light by ethidium bromide
staining. Genotype was confirmed by direct sequence
analysis with the use of a dye terminator kit on an ABI 377
automated sequencer. To prevent observer bias, the investigator was
unaware of sample origin and all gels were cross checked by a separate
individual. Valid genotyping was obtained in a total of 428 black
individuals (93.2%). The characteristics of those not
genotyped (6.8%) did not differ from the rest of the
population (data not shown).
Statistical Analysis
The calculation of allele frequency to test for
Hardy-Weinberg equilibrium was performed by use of standard
methods.12 Associations between hypertension and
genotype were tested with 
2 tests.
Multiple logistic regression was used to test the effect of
genotype on the likelihood of hypertension while controlling
for confounding factors. Accordingly, the association between presence
of hypertension and genotype was tested by calculating odds
ratios (ORs) under a dominant model with scores of 0 for CC and 1 for
the TC and the TT genotypes combined. When appropriate, 1-way
ANCOVA was used for comparisons of group means adjusted for
confounders. To study the attributable risk of hypertension to the
presence of the T variant, population-attributable risk percent (PAR%)
was estimated as
follows:
where PrevE is the prevalence of the
exposure (T allele frequency) and OR is the estimated OR of the
association between the T allele and the presence of
hypertension.13 Group values are given as mean±SE.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Frequencies of genotypes CC, CT, and TT in the whole group were in Hardy-Weinberg equilibrium with observed frequencies of 4.0% (n=17), 33.6% (n=144), and 62.4% (n=267), respectively, and frequencies of 20.8% for C and 79.2% for T allele. No significant difference existed in frequencies between West Africans (n=158; 2.5%, 30.4%, and 67.1% for CC, CT, and TT, respectively) or Caribbeans (n=270; 4.8%, 35.6%, and 59.6% for CC, CT, and TT, respectively). No significant differences existed in age- and sex-adjusted characteristics by genotype (Table 1). A higher prevalence of hypertension was seen among the carriers of the T variant (both as heterozygotes and homozygotes) compared with the CC genotype, even after adjustment for age, sex, and body mass index (
2 for trend=2.91; P=0.08) (Table 2). Although the association was of
borderline significance, the estimate of effect suggested the
possibility of a dominant model for the T allele. In addition, the
blood pressures (when adjusted for age and sex) tended to be higher in
those with the 825T variant (Table 1). Although it was not
statistically significant, this tendency toward increases in blood
pressure in those with the T allele was also found in the 279
participants who were not on antihypertensive therapy (TT,
138.0±1.5/87.5±0.7 mm Hg and CT, 138.6±1.9/86.5±1.0
mm Hg versus CC, 131.0±5.5/84.7±2.8 mm Hg; P by
ANCOVA=0.43 and 0.49 for systolic and diastolic, respectively).
These findings suggested a dominant model for the T allele. Further
analyses were then performed by use of logistic regression
under an a priori defined dominant model for the T allele. The
results confirmed a significant and independent association between the
T allele and hypertension (Table 2). No interaction was
detected between sex, age, and body mass index. Serum electrolytes and
creatinine did not vary by genotype (Table 1). Age- and sex-adjusted plasma aldosterone levels
were also comparable across genotypes (Table 1). Similar
results were found in those not on treatment (data not shown).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study demonstrates a high frequency of the 825T allele in black people (79.2%; 95% CI, 76.5 to 81.9) compared with that reported in whites elsewhere2 3 4 5 (28.1%; 95% CI, 26.0 to 30.2)2 and in our own work (28.6%; 95% CI, 22.3 to 34.9 [Y.D., unpublished observation, 1999]). Moreover, the T allele is significantly associated with hypertension (Table 2), which suggests that this genetic variant could be a predisposing factor to hypertension in blacks. The strength of the association between the T allele and hypertension is compatible with that reported in 3 separate studies in whites (OR, 1.44 [95% CI, 1.09 to 1.90]2 ; OR, 1.5 [95% CI, 1.1 to 2.2]3 ; and OR, 2.3 [95% CI, 1.7 to 3.3]).4 High blood pressure is a serious problem in African and Caribbean people living in the UK and affects almost 1 in 2 by the age of 50.10 14 Given the high prevalence of the T allele in blacks, an OR of even 2 would explain a high proportion of the hypertension occurring in blacks. For example, if the T allele is causative and this doubles the risk of hypertension, given a frequency of the T allele of 0.80, the population-attributable risk is 44%, which indicates the proportion of hypertension in blacks attributable to this genetic variant.
Our study has several important aspects in addressing genetic variations within a population. It investigates for the first time the frequency of the C825T polymorphism in a population-based sample of black people of African origin. It examines first-generation immigrants with both parents born in the country of origin and belonging to the same ethnic group, thus reducing the potential effect arising from an unknown degree of admixture. The sample is from the same geographic area, thereby mitigating the potential effects of differences in environmental background.
G protein–containing subunits are involved in several types of transduction pathways.1 Hence, defects in G protein signaling could lead to hypertension through a multiplicity of mechanisms that operate at distinct levels. Expression of the T allele leads to an in-frame deletion of the Gß3 protein, which is associated with enhanced sensitivity of Gi proteins to receptor activation. Therefore, a higher blood pressure could arise from increased sensitivity to vasoactive pressor hormones known to transmit their signals through Gß3 proteins.15 Alternatively, an increase in renal sodium reabsorption through increased activity of the renal Na+-H+ exchanger could mediate the rise in blood pressure.2 In our study, we did not detect any difference in plasma electrolytes and aldosterone according to C825T genotype. However, plasma aldosterone is not a sensitive marker of volume status and the effect on sodium balance remains a possibility.
In summary, this study shows a high frequency of the 825T allele in black people and provides preliminary evidence that the 825T allele may be a significant susceptibility factor for the development of hypertension in blacks. However, given the high frequency of the T allele, further work is needed to determine more precisely its effect on hypertension in black people. Although these findings clearly require independent confirmation, together with previous work,16 they highlight the possible contribution of variants in genes regulating renal sodium handling in the development of hypertension in blacks.
|
Acknowledgments |
|---|
The Wandsworth Heart & Stroke Study has received support from the British Heart Foundation, the British Diabetic Association, The Stroke Association, the NHS R&D Directorate, the SW Thames Regional Health Authority, and the former Wandsworth Health Authority. We thank Michael J. Rothwell for DNA extraction, Elizabeth J. Folkerd for plasma aldosterone measurements, and the staff in the Blood Pressure Unit for support and assistance. G.A.S., N.D.C., D.G.C., and F.P.C. are members of the St George’s Cardiovascular Research Group.
Received June 17, 1999; first decision July 6, 1999; accepted August 6, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Bohm SK, Grady EF, Bunnet NW. Regulatory mechanisms that modulate signalling by G-protein-coupled receptors. Biochem J. 1997;322:1–18.
2. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R, Sharma AM, Ritz E, Wichmann H-E, 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]
3.
Beige J, Hohenbleicher H, Distler A, Sharma AM.
G-protein beta3 subunit C825T variant and ambulatory blood pressure in
essential hypertension. Hypertension. 1999;33:1049–1051.
4.
Benjafield AV, Jeyasingam CL, Nyholt DR, Griffiths LR,
Morris BJ. G-protein beta3 subunit gene (GNB3) variant in causation of
essential hypertension. Hypertension. 1998;32:1094–1097.
5.
Brand E, Herrmann S-M, Nicaud V, Ruidavets J-B, Evans
A, Arveiler D, Luc G, Plouin P-F, Tiret L, Cambien F. The 825C/T
polymorphism of the G-protein subunit ß3 is not related to
hypertension. Hypertension. 1999;33:1175–1178.
6.
Rosskopf D, Dusing R, Siffert W. Membrane
sodium-proton exchange and primary hypertension.
Hypertension. 1993;21:607–617.
7.
Schunkert H, Hense HW, Doring A, Riegger GA, Siffert
W. Association between a polymorphism in the G protein beta3
subunit gene and lower renin and elevated diastolic blood
pressure levels. Hypertension. 1998;32:510–513.
8. Weinberger MH. Hypertension in African Americans: the role of sodium chloride and extracellular fluid volume. Semin Nephrol. 1996;16:110–116.[Medline] [Order article via Infotrieve]
9. Cappuccio FP, Cook DG, Atkinson RW, Wicks PD. The Wandsworth Heart & Stroke Study: a population-based survey of cardiovascular risk factors in different ethnic groups: methods and baseline findings. Nutr Metab Cardiovasc Dis. 1998;8:371–385.
10.
Cappuccio FP, Cook DG, Atkinson RW, Strazzullo P.
Prevalence, detection and management of cardiovascular
risk factors in different ethnic groups in South London.
Heart. 1997;78:555–563.
11. Sagnella GA, Rothwell MJ, Onipinla AK, Wicks PD, Cook DG, Cappuccio FP. A population study of ethnic variations in the angiotensin converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism. J Hypertens. 1999;17:657–664.[Medline] [Order article via Infotrieve]
12. Falkoner DS, Mackay TFC. Genetic constitution of a population. Introduction to Quantitative Genetics. 4th ed. Essex, England; Longman, Scientific & Technical: 1996:1–22.
13. Hennekens CH, Buring JE. Measures of disease frequency and association. Epidemiology in Medicine. Boston, Mass/Toronto, Canada; Little, Brown, and Co: 1987; 90–93.
14.
Stewart JA, Dundas R, Howard RS, Rudd AG, Wolfe CDA.
Ethnic differences in incidence of stroke: prospective study with
stroke register. BMJ. 1999;318:967–971.
15. Schiffrin EL. Intracellular signal transduction for vasoactive peptides in hypertension. Can J Physiol Pharmacol. 1994;72:954–962.[Medline] [Order article via Infotrieve]
16. Baker EH, Dong YB, Sagnella GA, Rothwell M, Onipinla AK, Markandu ND, Cappuccio FP, Cook DG, Persu A, Corvol P, Jeunemaitre X, Carter ND, MacGregor GA. Association of hypertension with T594 M mutation of ß sub-unit of epithelial sodium channels in black people resident in London. Lancet. 1998;351:1388–1392.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  N. Eynon, J. Oliveira, Y. Meckel, M. Sagiv, C. Yamin, M. Sagiv, R. Amir, and J. A. Duarte The guanine nucleotide binding protein \#946; polypeptide 3 gene C825T polymorphism is associated with elite endurance athletes Exp Physiol, March 1, 2009; 94(3): 344 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. P. Havranek and F. A. Masoudi What we're talking about when we talk about race J. Am. Coll. Cardiol., February 4, 2004; 43(3): 436 - 437. [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 F. P Cappuccio, A. Barbato, and S. M Kerry Hypertension, diabetes and cardiovascular risk in ethnic minorities in the UK The British Journal of Diabetes & Vascular Disease, July 1, 2003; 3(4): 286 - 293. [Abstract] [PDF]
|
|
|
|
|
|
H. Snieder, G. A. Harshfield, and F. A. Treiber Heritability of Blood Pressure and Hemodynamics in African- and European-American Youth Hypertension, June 1, 2003; 41(6): 1196 - 1201. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||