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(Hypertension. 1998;32:510-513.)
© 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

Heribert Schunkert; Hans-Werner Hense; Angela Döring; Günter A. J. Riegger; ; Winfried Siffert

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

	Abstract

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Abstract—G_i 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 (CT) 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 G_ß3 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

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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, G_i-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 G_i2, G_i3, G_ß1, and G_ß2 were screened for polymorphisms, but were found to be without alterations in affected hypertensive subjects.³ However, molecular analysis of G_ß3 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 G_i proteins was tightly associated with this splice variant and expression of recombinant mutated G_ß3 in insect cells allowed the modified protein to be generated in vitro.⁴

Potential implications of the G_ß3 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 G_ß3 825T polymorphism and arterial blood pressure in a sample of the general population. Furthermore, we speculated that enhanced G_i 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 G_ß3 825T genotype.

	Methods

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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.

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-tetrahydroaldosterone and 3,5ß-tetrahydroaldosterone is 4.2% and 0.3%, respectively. All other steroids cross-react to <0.1%.

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
Anthropometric data of subjects were compared according to the G_ß3 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 G_ß3 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 G_ß3 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 G_ß3 825T allele.

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 G_ß3 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 G_ß3 C825T polymorphism. Probability values are reported for each test and statistical model, including 95% confidence intervals for the relative risk estimates.

	Results

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In the entire cohort and the subgroups presented below, the genotype distribution of the G_ß3 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 G_ß3 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 this window] [in a new window]   Table 1. Anthropometric and Biochemical Data in Participants Without Antihypertensive Treatment and Hypertension Status in All Participants

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 G_ß3 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). Furthermore, significant associations between the G_ß3 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 this window] [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.

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), a finding that persisted after adjustment for age, gender, and body mass index (Table 2).

View this table: [in this window] [in a new window]   Table 2. Adjusted Risk for Presence of Arterial Hypertension or Antihypertensive Drug Treatment

	Discussion

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In the present study, carriers of a frequent polymorphism at position 825 of the G_ß3 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

Given the nature of the underlying polymorphism, namely an in-frame deletion of the G_ß3 protein associated with enhanced signaling via pertussis toxin–sensitive G_i 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 ₂-adrenoceptors, angiotensin II, and thrombin) are known to transmit some of their effects via pertussis toxin–sensitive G_i proteins.^{10 11 12} Thus, these vasoconstrictors, if activated, may cause enhanced vascular resistance in individuals carrying the mutated G_ß3 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 G_i protein–dependent pathways.³

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 G_i proteins. Thus, enhanced G_i 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 G_i 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 G_ß3 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 G_ß3 825T allele with higher diastolic blood pressure level, lower renin level, and an elevated aldosterone to renin ratio. Furthermore, these effects of the G_ß3 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 G_ß3 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 G_ß3 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 G_ß3 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 G_i protein–mediated signaling has allowed investigators to discriminate candidate genes and thereby to discover the polymorphism in the G_ß3 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 G_ß3 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 G_ß3 subunit gene that had been shown to enhance G_i protein–related transmembrane signaling.

	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.

Received January 23, 1998; first decision February 26, 1998; accepted May 21, 1998.

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				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]

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