Published online before print February 24, 2003, doi: 10.1161/01.HYP.0000057010.27011.2C
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(Hypertension. 2003;41:398.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
ACE and 
-Adducin Polymorphism as Markers of Individual Response to Diuretic Therapy
From the Department of Nephrology and Graduate School of Nephrology Universita’ Vita e Salute, Milan; and Division of Nephrology, Dialysis, and Hypertension, S. Raffaele Hospital, Milan, Italy.
Correspondence to Maria Teresa Sciarrone, Chair of Nephrology, University Vita Salute, S. Raffaele Hospital, via Olgettina 60, 20132 Milan, Italy. E-mail sciarronealibrandi.mariateresa{at}hsr.it
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Abstract |
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Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and
-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and -adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of -adducin had the largest MBP decrease with treatment (12.7±1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460Gly+DD, with the least MBP decrease (3.4±1.7 mm Hg). -Adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.
Key Words: genetics • renin-angiotensin system • sodium • polymorphism • hypertension, essential
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Introduction |
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The therapy of hypertension suffers from a discrepancy between the extensive analysis and reports of the beneficial effects of blood pressure (BP) lowering in the whole population and the relative lack of such an extensive effort and scientific rigor in investigating the heterogeneity of individual response to pharmacological treatment. Variation in individual response to therapy is a well-known phenomenon in clinical practice. This discrepancy contributes to the high rate of therapy discontinuation and/or underdosing because of poor efficacy or unwanted side effects.1–3 The study of the renin profile and the vasoconstriction-volume analysis by Laragh et al4,5 represents pioneering work in the identification of the sources of interindividual variation in response to therapy. Blood pressure response to an antihypertensive agent can be considered a combination of the pharmacological effect of the drug and the physiological reactions of the patient. Salt loss with consequent volume depletion induced by diet or diuretic treatment in some patients may be counterbalanced by hyperactivation of the renin-angiotensin system (RAS) determining vasoconstriction and increased adrenergic tone.6 Therefore, considering the relationship between volume and the RAS in the pathogenesis of essential hypertension7 and in the response to drugs, the main question is: What determines the variability from one patient to another in the response to diuretics? What is the respective contribute of pharmacokinetics or pharmacodynamics to this variability? Genetics may help in defining the respective contributes of these 2 mechanisms. When the contribution of the former is defined, the latter may also help in dissecting the genetic complexity of hypertension, since the association between a genetic polymorphism and the response to treatment may provide insight in the pathogenetic mechanisms. Because of the importance of volume and vasoconstriction, sodium balance, and RAS activation as mechanisms underlying hypertension, diuretics can be a good example of application of this approach.8–11
We chose ACE I/D and -adducin Gly460Trp polymorphisms, even though we are aware that their role in the pathogenesis of hypertension is not yet fully elucidated, because of our previous demonstration of their interaction on renal sodium handling and blood pressure regulation.12 This interaction may be due to the fact that ACE I/D polymorphism affects RAS activation after sodium depletion,6 thus limiting the BP fall. Conversely, -adducin Gly460Trp polymorphism influences the constitutive capacity of the kidney to reabsorb sodium,8 thus implying a modulation of the BP responsiveness to a drug such as HCTZ, which inhibits such renal mechanism. In our work, such polymorphisms were considered both separately and together.
Because many factors affect the genotype-phenotype relationshp (environment, stage of disease, previous therapy, population admixture, and so forth), we studied only newly discovered and never-treated patients with mild hypertension to avoid the interference of previous therapy and of the stage of the disease. All participants were recruited in our outpatient clinic.
We found that hypertensive individuals carrying at least one I allele of ACE and at least one 460Trp allele of -adducin had the largest BP decrease after 2 months of HCTZ treatment.
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Methods |
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Eighty-seven patients with essential hypertension (office BP >140/95 but <160/110 mm Hg in at least 3 consecutive visits at weekly intervals) were enrolled after exclusion of secondary hypertension. After the 1-month run-in phase, the study protocol consisted of 2 months of treatment, the first with 12.5 mg and the second with 25.0 mg HCTZ die. During 1 month before the 2 months of therapy, patients were advised to keep a diet containing a salt intake of
150 mmol daily, which is not much different from the usual sodium intake of the population living in the Milan area (checked by measuring 24-hour urinary sodium excretion). BP was always recorded by the same investigator between 8:00 and 10:00 AM, about 24 hours after the last HCTZ dose. The last 3 of 10 BP measures taken after clinical examination were averaged and used in the analysis. The response to therapy was computed as the difference between the average of the last 3 BP values at the last pretreatment visit and the average of the last 3 BP values after 1 month of 12.5 mg HCTZ and after 1 month of 25 mg HCTZ. Mean BP (MBP) was computed as diastolic BP+(systolic BP-diastolic BP)/3. Approval by the Ethics Committee of San Raffaele Hospital and the patient’s informed consent were obtained.
Determination of ACE and -Addicin Genotype
DNA was extracted from blood samples according to standard protocols.13
The ACE gene I/D polymorphism and -adducin polymorphism were evaluated according to published methods.14,8
Statistical Analysis
Results are expressed as mean±SEM. Data were analyzed by the Student t test and by 1-way ANOVA (with Student-Newman-Keuls multiple comparisons test). A 
2 contingency test was used to assess differences in relative frequencies between genotypes. Univariate mixed factorial ANOVA for repeated measurements (covarying for gender, age, and body mass index [BMI]) (RM-ANOVA) was used to analyze the BP decrease with treatment, with one fixed factor within patients (time at 3 levels: basal, month 1 with 12.5 mg/d HCTZ, and month 2 with 25 mg/d HCTZ), 2 fixed factors between patients (group 1 at 3 levels: ACE genotype II; ID and DD or, alternatively at 2 levels, when dominance was tested (see below), and group 2 -adducin at 2 levels Gly460Gly and Gly460Trp + Trp460Trp, since we already demonstrated that the effect of the Trp allele on the BP decrease with HCTZ is dominant.8,15 In the present sample, the Trp460Trp number was 3 (too few to allow independent analysis), and "patient" was used as a random factor nested into the group factor, with Greenhouse Geisser correction for degrees of freedom.
Power Considerations
A power calculation was performed a priori by using the data of a previous study8 but considering only individuals recruited in Milan to predict the number of patients to treat with the a priori hypothesis that besides -adducin 460Trp allele, ACE I allele also could be associated with a larger BP decrease with HCTZ treatment. Twelve of 27 (44% of the sample) had either the least favorable (7 Gly460Gly + DD) or the most favorable (5 at least one 460Trp and one I allele) combination of genotypes. From those figures, we estimated that a sample of 86 patients would have 99% power with =0.05 to detect that carriers of at least one 460Trp and at least one I allele were more respondent to HCTZ than Gly460Gly+DD ones or that were more respondent than the remainder of the sample. Statistical analysis was performed with SPSS (version 10) and with G power 2.1.216 on an Apple Macintosh G3 Personal Computer.
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Results |
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We enrolled 87 patients (75 men and 12 women). One patient withdrew his consent before the end of the first month of treatment (HCTZ 12.5 mg).
The main clinical and biochemical characteristics of the patients who completed the study as a whole and according to ACE and -adducin genotype are summarized in Tables 1 through 4. A marginal significance was observed for height when data were analyzed according to ACE genotype and for PRA, when they were analyzed according to -adducin genotype, the latter confirming previous observations.8
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Control for deviation from the Hardy-Weinberg equilibrium gave nonsignificant results (P=0.995 for ACE and P=0.997 for -adducin), and the frequency of the ACE and -adducin alleles (I=0.40; D=0.60, for ACE and 460Gly=0.81; 460Trp =0.19 for -adducin) was similar to one obtained in a random sample of 200 individuals of similar age that we collected in the Milano area (I=0.38; D=0.62; 460Gly=0.79; 460Trp =0.21).
A significantly different trend in MBP decrease after 2 months of HCTZ was observed for ACE and for -adducin (RM-ANOVA, P=0.049, codominant model for ACE and P=0.002 for -adducin, with 460Trp dominant) when analyzed alone. The identical MBP decrease of II and ID patients (Figure 1) led us to test a recessive model for the D allele. II+ID were then analyzed together and compared with DD patients. Also in this case, a significantly different trend was observed (RM-ANOVA P=0.013 recessive model). The analysis was then repeated, entering ACE (D recessive) and -adducin (460Trp dominant) together as between-subject factors. The combination of genotypes was chosen according to the fact that carriers of 460Trp respond more to diuretic treatment (460Trp dominant)8 and that carriers of the D allele have increased PRA with volume depletion17 and blood pressure after angiotensin I infusion.18 In this way, we speculated that the hypotensive effect of incremental diuretic doses would be damped in carriers of the D allele.
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The independent contribution of the 2 genes remained significant, with no interaction (Table 5), indicating a pure additive effect without epistasis. The absolute MBP decrease was significant after 1 month for -adducin (P=0.005) and after 2 months for -adducin and ACE (P=0.003 and P=0.02, respectively, see Figure 1).
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In our previous study, we arbitrarily defined responders to this experimental protocol as patients whose MBP decreased >15 mm Hg at the end of the second month of treatment.8 By applying the same criteria to the present data set, 20 of 86 patients were classified as responders (23%). The responder rate doubled when considering only individuals carrying at least one I and one 460Trp allele (9 of 21, 43%, with a positive predictive value of 52%) but was reduced to 1 of 22 (4%) in those with the Gly460Gly+DD genotype. Compared with the latter, whose MBP decrease was only 3.43±1.7 mm Hg, those carrying at least one I and one 460Trp allele had an odds ratio of being respondent to HCTZ of 15.75 (2.06 to 57.63, 95% CI, 2=8.63), with a MBP decrease of 12.7±1.9 mm Hg (Figure 2).
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There were no significant differences between body weight changes according to the different ACE and -adducin genotypes after treatment.
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Discussion |
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Our data show that the magnitude of blood pressure fall after HCTZ is strongly influenced by ACE I/D and
-adducin Gly460Trp polymorphisms. These findings may have both theoretical and practical implications, provided that confounding factors may be reasonably excluded or properly understood. These results were obtained in a homogeneous group of newly discovered white hypertensive patients, all selected and followed up in the same unit by the same 2 physicians throughout all the study. Therefore the stage of the disease, the carry over effects of previous therapy, and some environmental factors could reasonably be excluded as a source of variation. Moreover, body weight, age, gender, and basal BP were not different among the various subgroups. To use the magnitude of the blood pressure fall as an intermediate phenotype to dissect genetic complexity, we have to exclude an influence of these 2 genotypes on the pharmacokinetics and metabolism of hydrochlorothiazide. This exclusion is probable, since the dose-effect relationship of HCTZ is very flat and poorly related to plasma levels, implying a relatively modest influence of the metabolism on pharmacodynamics.19
The major finding of our work is the significantly greater blood pressure fall observed in carriers of the genotype DI or II+Gly460Trp or Trp460Trp compared with carriers of the genotype DD+Gly460Gly (-12.7±1.9 mm Hg versus -3.43±1.7 mm Hg) after chronic diuretic treatment. Considering arbitrary definition of responders and a MBP decrease >15 mm Hg (identical to the one already proposed8), the whole group had 23% responders, but this value became 4% in the least responsive group (DD+Gly460Gly) and 43% in the most responsive group (DI or II+Gly460Trp or Trp460Trp), with an odds ratio of being as responder of 15.75 when the latter group was compared with the first. In fact, our data confirm the already known remarkable heterogeneity in the individual BP response to sodium depletion or antihypertensive drugs that still represents an obstacle in the therapeutic approach to hypertension. Therefore, the BP fall according to the different combinations of genotypes may be due to an interaction of HCTZ, with the pressor mechanism triggered by the genotypes.
ACE and -adducin polymorphisms should work at 2 different biological levels. The activation of the RAS is probably one of the most powerful mechanisms limiting the BP fall after sodium depletion induced by a low salt diet6 or diuretic therapy. There is a general agreement that the D allele of ACE is associated with increased plasma20 and tissues levels of ACE.18,21–23 The RAS is mostly a paracrine and autocrine system, and the plasma level of its constituents poorly reflect its activity. Also, if the biological meaning of larger ACE activity is still controversial, the D allele has been often associated with the worsening of cardiovascular and renal prognosis,24,25 whereas ACE inhibitors improve it.26
The relation between salt-sensitive hypertension and I/D ACE gene polymorphism has been previously tested in several studies with controversial results. Kojima et al17 reported a lack of association between the ACE I/D genotype and salt sensitivity in patients with essential hypertension, but they observed that PRA increase after salt restriction is greater in patients with the DD genotype. Hiraga et al9 instead reported a significant association between salt sensitivity and ACE genotype that has been confirmed by Giner et al,10 who found that II patients are the most responsive to acute changes in sodium intake.
These different results may be related to the protocols used as in all these trials; the antihypertensive therapy was stopped before the beginning of the study, and the patients underwent a washout period from 10 days to 4 weeks. In fact, the carryover effect of a treatment influences not only blood pressure level but also involves other pressure mechanisms. Swart et al27 reported that the plasma renin response to bendrofluazide was still abnormal after 1 month of washout from a chronic diuretic therapy. Therefore, in our work, we limited patient recruitment, choosing only subjects never treated before to avoid the influence of previous treatment as a confounding factor.
We speculate that D allele-associated RAS hyperactivation is the most likely explanation for the lesser BP decrease with HCTZ in our DD patients (Figure 1A), which becomes entirely visible when both the time elapsed from the start of the diuretic treatment and the doubling of its dose should have led to larger sodium volume depletion.
The -adducin 460Trp allele instead is associated with a larger BP increase after saline infusion,12 faster proximal tubular reabsorption,28 lower PRA, and larger BP fall after diuretics,8 with faster sodium transport across erythrocyte membranes and lower intraerythrocytic sodium content.15 Also, in MHS rats, -adducin polymorphism affects sodium transport across the cell membrane.29 Therefore, HCTZ appears to specifically counteract the genetically determined pressor mechanism (increased tubular reabsorption) at work in 460Trp patients and in MHS rats, causing larger BP fall.
If we admit that the 460Trp allele of -adducin shifts the pressure natriuresis mechanism to the right by increasing the constitutive capacity of the tubuli to reabsorb sodium just as a clip on the renal artery of a sole remaining kidney,30 than we can propose some analogy between these 2 conditions.
In experimental renal artery stenosis, clip removal normalizes all the hemodynamic and hormonal changes without activation of compensatory mechanisms, which, conversely, are activated if blood pressure is reduced with other maneuvers. Similarly, HCTZ treatment may activate the RAS system much less in 460Trp allele-dependent hypertension than in Gly460Gly patients, in which other primary pressor mechanisms are at work. Conversely, ACE II patients may respond more to HCTZ because their homeostatic RAS activation is less reactive.
Besides the beneficial effect of lowering BP in a subgroup of patients, like any other maneuver of sodium depletion, diuretic therapy may switch on potential risk factors related to RAS activation such as insulin resistance and increase of serum catecholamines and lipids.31 Therefore, the global cardiovascular risk may even increase in the subgroup of patients in which no significant BP fall is achieved. The well-accepted notion that diuretics confer relative reductions in stroke and coronary heart disease risk in the whole population of patients does not exclude the possibility that because of heterogeneity, the remarkable beneficial effects in a subgroup of patients may override a negative one in another subgroup in which a long-term therapy may increase the global risk factor.
The findings described here support the notion that both ACE and -adducin polymorphisms may help in predicting the interindividual degree of BP response to diuretics, which, in turn, may help in understanding the interaction between these 2 genes.
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Acknowledgments |
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This work was supported in part by grants from Ministero Università e Ricerca Scientifica of Italy (FIRST years 1998 to 2000 (to C.B. and D.C.), by Cofin Grants MM06A92341_005 (to D.C.) and MM06A9241_001 (to G.B.), and by a grant from Eurnetgen, EC-funded research (Grant QLG1-2000-01137).
Received March 12, 2002; first decision April 9, 2002; accepted January 8, 2003.
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G. Bianchi, P. Ferrari, and J. A. Staessen Adducin Polymorphism: Detection and Impact on Hypertension and Related Disorders Hypertension, March 1, 2005; 45(3): 331 - 340. [Abstract] [Full Text] [PDF]
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M. H. Weinberger More on the Sodium Saga Hypertension, November 1, 2004; 44(5): 609 - 611. [Full Text] [PDF]
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E. Beeks, M. M. van der Klauw, A. A. Kroon, W. Spiering, M. J.M.J. Fuss-Lejeune, and P. W. de Leeuw {alpha}-Adducin Gly460Trp Polymorphism and Renal Hemodynamics in Essential Hypertension Hypertension, October 1, 2004; 44(4): 419 - 423. [Abstract] [Full Text] [PDF]
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F. C. Luft Geneticism of Essential Hypertension Hypertension, June 1, 2004; 43(6): 1155 - 1159. [Full Text] [PDF]
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P. Manunta and G. Bianchi Low-Salt Diet and Diuretic Effect on Blood Pressure and Organ Damage J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S43 - 46. [Abstract] [Full Text]
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I. Narita, S. Goto, N. Saito, J. Song, J. Ajiro, F. Sato, D. Saga, D. Kondo, K. Akazawa, M. Sakatsume, et al. Interaction Between ACE and ADD1 Gene Polymorphisms in the Progression of IgA Nephropathy in Japanese Patients Hypertension, September 1, 2003; 42(3): 304 - 309. [Abstract] [Full Text] [PDF]
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