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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0049
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 5008-5012
Copyright © 2006 by The Endocrine Society

CYP11B2 –344T/C Gene Polymorphism and Blood Pressure in Patients with Acromegaly

Paolo Mulatero, Franco Veglio, Pietro Maffei, Marta Bondanelli, Silvia Bovio, Fulvia Daffara, Giannina Leotta, Alberto Angeli, Chiara Calvo, Chiara Martini, Ettore C. degli Uberti and Massimo Terzolo

Division of Internal Medicine and Hypertension (P.Mu., F.V., G.L., C.C.), San Vito Hospital, and Medicina Interna I (S.B., F.D., A.A., M.T.), Dipartimento di Scienze Cliniche e Biologiche, S. Luigi Hospital, Orbassano, University of Torino, 10133 Torino, Italy; Clinica Medica III (P.Ma., C.M.), Dipartimento di Scienze Mediche e Chirurgiche, University of Padua, 35100 Padua, Italy; and Department of Biomedical Sciences and Advanced Therapies (M.B., E.C.d.U.), Section of Endocrinology, University of Ferrara, 44100 Ferrara, Italy

Address all correspondence and requests for reprints to: Paolo Mulatero, Hypertension Unit, Ospedale San Vito, Strada San Vito 34, 10133 Torino, Italy. E-mail: paolo.mulatero{at}libero.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The pathogenesis of increased blood pressure (BP) in acromegaly is unclear, and the role of IGF-I levels and the renin-angiotensin-aldosterone system (RAAS) in this disease remains controversial.

Objective and Design: The aim of this study was to investigate the role of gene polymorphisms of the RAAS and involved in sodium handling on BP in acromegaly.

Setting and Patients: We conducted a multicentric retrospective study that included 100 consecutive patients with acromegaly referred during the period 2000–2003.

Intervention: All patients were genotyped for ACE I/D, AGT M235T, CYP11B2 –344T/C, B2R –58T/C, and {alpha}-adducin G460W polymorphisms.

Main Outcome Measure: We assessed the prevalence of hypertension and BP according to the genotype.

Results: Patients with the CYP11B2 –344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4–11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 –344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Patients with the –344CC genotype displayed a significant increase in systolic BP (10.2 ± 4.3 mm Hg; P = 0.02) but not a significant increase in diastolic BP (2.6 ± 2.6 mm Hg; P = 0.32) compared with patients with the CT/TT genotype.

Conclusions: We have shown an association of the –344T/C CYP11B2 gene polymorphism with BP in patients affected by acromegaly. These findings suggest that the RAAS is implicated in the pathogenesis of hypertension in acromegaly.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACROMEGALY IS AN infrequent disease attributable to an endogenous excess of GH and IGF-I (1, 2). Acromegaly is associated with a 2- to 3-fold increased morbidity and reduced life expectancy. Excess mortality is mostly due to cardiovascular and cerebrovascular disease and can be reduced when serum GH and IGF-I are effectively lowered by treatment (3, 4, 5). Analysis of determinants of mortality outcomes indicates that approximately 60% of acromegalic patients die of cardiovascular complications, and elevated GH concentrations, hypertension, and heart disease have a major impact on survival (4, 5).

The prevalence of hypertension in acromegalic patients has been reported to range from 18–57% across the different series (4, 6, 7, 8, 9, 10). This discrepancy is not surprising considering that the published studies are heterogeneous with respect to the demographic and clinical features of the patients included. Moreover, variable criteria to define hypertension or different procedures for measuring blood pressure (BP) have been employed (8). The relationship between GH and IGF-I excess and hypertension is demonstrated by the parallel lowering of GH and BP after successful treatment of acromegaly (4, 8), although a direct correlation between GH or IGF-I, or both, and BP has not been consistently demonstrated (4, 6, 7, 10). The pathogenesis of hypertension in acromegaly is not fully understood; the mechanisms putatively responsible for the increased BP include expansion of plasma volume due to increased sodium reabsorption (11, 12), potentially mediated by direct activation of distal tubular sodium channels by IGF-I (13). However, studies of the renin-angiotensin-aldosterone system (RAAS) in acromegaly have produced conflicting results (8, 12, 14, 15, 16, 17).

To our knowledge, the contribution of genetic factors to the development of hypertension in acromegaly has not been previously explored. To address this issue, we studied the polymorphisms of genes belonging to the RAAS, such as angiotensinogen (AGT), angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2), and two genes involved in the control of sodium handling, {alpha}-adducin and the bradykinin B2 receptor (B2R). {alpha}-Adducin is a cytoskeletal protein involved in cell membrane ion transport that modulates the Na+/K+ pump activity (18, 19), whereas B2R mediates the known cardiovascular actions of bradykinin, vasodilation, and natriuresis (20, 21). The T235M polymorphism in the AGT gene has been previously implicated in essential hypertension (22). The T235 allele, found at increased frequency in samples of individuals with essential hypertension, is in tight linkage disequilibrium with a nucleotide substitution (6A/C) in the promoter of the angiotensinogen gene that increases its basal transcription rate in vitro (23), resulting in increased circulating levels of angiotensinogen. The D allele of the I/D polymorphism in the ACE gene has been associated in some studies with an increased risk for cardiovascular diseases and with raised circulating and cellular concentrations of ACE (24). The C-344T polymorphism of the CYP11B2 gene promoter has been hypothesized to be associated with a variation in the transcription rate of the gene. This polymorphism has been described in association with hypertension and aldosterone secretion in different populations (25, 26, 27, 28, 29). In humans, a genetic variant (G460W) of the {alpha}-adducin gene has been found to be associated with essential hypertension and renal sodium handling (30, 31). A C/T polymorphism at position –58 of the B2R gene promoter has been described, where the –58C allele results in a decrease in the rate of gene transcription (32). In addition, the –58C variant is associated with hypertension in African-Americans (33), a population with a high prevalence of salt-sensitive hypertension.

The aim of the present study was to investigate in a large series of patients with acromegaly the frequency of polymorphisms of genes belonging to the RAAS and of genes involved in the control of sodium handling and their relationship with BP.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We performed a retrospective cross-sectional analysis on 100 patients with acromegaly who were consecutively admitted from January 1, 2000, through December 31, 2003, to three different centers in Northern Italy (Ferrara, Padova, and Torino). Demographic and clinical features of the acromegalic patients are described in Table 1Go. Thirty-nine patients were newly diagnosed to have acromegaly, whereas the remainder were referred for a follow-up visit after a median period of 48 months (range, 24–120 months) from diagnosis. In all patients, the diagnosis of acromegaly was established in participating centers on the basis of typical clinical features and the following data: 1) high serum GH concentrations (>2.5 µg/liter as a mean of at least five samplings), 2) GH concentrations not suppressed less than 1 µg/liter after administration of an oral glucose load (75 g), 3) circulating IGF-I levels above the upper limit of the age-related reference range developed by the local laboratory of each center, and 4) demonstration of a pituitary tumor at neuroradiological imaging by computed tomographic scan or magnetic resonance. Patients who underwent pituitary surgery had histological confirmation of pituitary adenoma with positive tissue immunostaining for GH. Circulating GH and IGF-I levels were measured in-house at each participating center by immunoassays using commercially available reagents. GH was measured by immunoradiometric assay with reagents supplied by Nichols Institute (San Juan Capistrano, CA) at Ferrara and with reagents supplied by DiaSorin (Saluggia, Italy) at Torino. The detection limit was 0.02 µg/liter and 0.2 µg/liter, respectively, with intra- and interassay variation coefficients of 3.9–4.2 and 5.5–7.2%, respectively. At Padova, GH was measured by chemiluminescence with reagents supplied by Medical System (Milano, Italy). The detection limit was 0.05 µg/liter, with intra- and interassay variation coefficients of 4.0 and 6.5%, respectively. Plasma IGF-I was determined by RIA after acid-ethanol extraction from EDTA plasma using commercially available kits supplied by Medgenix Diagnostic S.A (Fleurus, Belgium) at Ferrara and Nichols Institute (San Juan Capistrano, CA) at Torino. The sensitivity of the methods was 0.1 µg/liter. The intra- and interassay coefficients of variation were 3.0–6.1 and 8.4–9.6%. At Padova, IGF-I was measured by chemiluminescence with reagents supplied by DiaSorin. The detection limit was 0.6 µg/liter, with intra- and interassay variation coefficients of 5.6 and 7.7%, respectively. Specific gender- and age-adjusted reference ranges of IGF-I concentrations were defined at each center in large groups of healthy subjects. Because of the multicentric nature of the study, IGF-I concentrations were expressed according to the following formula: [(x – y)/y] x 100, where x is the observed value and y is the corresponding sex- and age-adjusted upper normal limit. We chose not to use GH concentrations in the statistical analysis because absolute levels are not reliable when different assays are used (34). All the patients underwent blood withdrawal to obtain leukocyte DNA. Details concerning patients at the time of diagnosis, when the patients had not been previously treated by pituitary surgery or somatostatin analogs, were obtained retrospectively from their medical records.


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  		TABLE 1. Demographic and clinical features of the patients with acromegaly, with and without hypertension

 
All measurements were performed accordingly to the European Society of Hypertension-European Society of Cardiology guidelines (35). In particular, BP was recorded between 0800 and 1000 h after the patients had been sitting in a comfortable position in a quiet room for at least 15 min. Pulse pressure was calculated as systolic BP (SBP) – diastolic BP (DBP). Patients were considered hypertensive if SBP was at least 140 mm Hg and/or DBP was at least 90 mm Hg or they were under antihypertensive treatment.

A total of 120 normotensive volunteers of more than 55 yr of age without hypertensive first-degree relatives and 100 never-treated essential hypertensives recruited from the same area as the patients with acromegaly and matched for sex, age, and body mass index (BMI) served as controls. Some of the controls have been used in previously published studies (36, 37, 38, 39). All patients and controls were of Caucasian origin. The study was designed in agreement with the Declaration of Helsinki and was approved by the local ethical committees. The patients and subjects volunteered for the study and gave their informed consent for analysis of leukocyte DNA, and access to the collected information was obtained from all of the patients in accordance with national ethical rules.

Genotype analyses

Blood samples were withdrawn into EDTA-containing receptacles, and DNA was extracted as described elsewhere (39). The bradykinin B2 receptor C-58T was identified by PCR amplification and digestion with MaeIII; the {alpha}-adducin G460W polymorphism was identified by PCR amplification and digestion with BsaMI; the aldosterone synthase T-344C was identified by PCR amplification and digestion with HaeIII, and the angiotensinogen M235T polymorphism was identified by PCR amplification and digestion with Tth111I; the ACE I/D polymorphism was determined by PCR amplification; all of these methods have been described in detail previously (37, 38).

All genotyping was performed by a researcher who had no knowledge of the clinical parameters.

Statistical analyses

Statistical analysis was performed using Statistical Analysis Package (SAS Institute, Inc., Cary, NC). No deviations of genotype frequencies from Hardy-Weinberg equilibrium were observed for the alleles tested individually in each group.

We calculated means and SD for descriptive variables and proportions for categorical variables. To test for group differences of means, we used a one-way ANOVA and a Kruskal-Wallis test for parameters with normal and not normal distributions, respectively; to test for group differences of proportions, we used Fisher’s exact test.

To investigate the effect of the gene polymorphisms on BP, we performed a logistic regression analysis, considering as the response variable the presence or not of hypertension and as explanatory variables the five gene polymorphisms, together with normalized IGF-I levels and common confounding factors (age, gender, and BMI). In addition, we performed a linear regression analysis between BP (dependent variable) and the following independent variables: gene polymorphisms, normalized IGF-I levels, age, gender, and BMI. The analysis was performed for both SBP and DBP. A dichotomized variable hypertension (yes/no) was used in the analysis to circumvent the problem that many patients were on antihypertensive treatment at the time of BP recording. This may act as a confounder when using BP as a continuous variable. To correct for multiple comparisons, we used the Q program (40).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Effect of polymorphisms on the risk of hypertension

Fifty-two percent of the acromegalic patients displayed BP higher than 140 and/or 90 mm Hg at diagnosis. We performed a logistic regression to evaluate the role of the five gene polymorphisms, of normalized IGF-I levels, and of age, sex, and BMI on the risk of hypertension in patients with acromegaly. Patients with the CYP11B2 –344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes [odds ratio = 4.0; 95% confidence interval (CI) = 1.4–11.6; P = 0.01]; this result was still significant after correction for multiple comparisons (P = 0.04) (Table 2Go). Among the other variables, only age had a significant effect on the risk of hypertension (risk ratio = 1.1; 95% CI = 1.06–1.2; P < 0.0001) whereas sex, BMI, IGF-I levels, and all other polymorphisms did not display a significant effect on the risk of hypertension in patients with acromegaly (Table 2Go). Consistently, a significant proportion of patients with the CYP11B2 –344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003).


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  		TABLE 2. Logistic regression analysis

 
Effects of polymorphisms on BP

To evaluate the effect of the different variables on BP, we performed a linear regression analysis using SBP and DBP as dependent variables and the four gene polymorphisms, IGF-I levels, and age, sex, and BMI as independent variables. We observed that patients with the –344CC genotype displayed a significant increase in SBP (10.2 ± 4.3 mm Hg; P = 0.02) but not a significant increase in DBP (2.6 ± 2.6 mm Hg; P = 0.32) compared with patients with the CT/TT genotype (Table 3Go). Among the other variables, only age displayed a significant effect both on SBP and DBP (Table 3Go).


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  		TABLE 3. Linear regression analysis between BP (dependent variable) and other parameters

 
Polymorphisms in patients with acromegaly and controls

All genotypes were distributed according to the Hardy-Weinberg equilibrium in patients with acromegaly and controls. We did not find statistically significant differences in the distribution of the genotypes and of the alleles comparing patients with acromegaly and hypertensive and normotensive controls (data not shown). Furthermore, normotensive and hypertensive controls, after subdivision according to –344T/C genotype, did not show differences in SBP and DBP between genotypes. This rules out the possibility that the increased prevalence of the –344CC genotype in hypertensives with acromegaly was due to the increased prevalence of the CC genotype in the hypertensive population in general.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study showing an association between polymorphisms in candidate genes and BP in a large series of patients with acromegaly. However, we acknowledge the limitations of the retrospective nature of the study because the treatment for hypertension was not discontinued; thus, antihypertensive therapy may have affected BP in the different subgroups. Nonetheless, the present study may provide new insights on the pathophysiology of hypertension in acromegaly.

The prevalence of hypertension in acromegaly has been reported to range from 18–57%; this discrepancy is mainly the result of different cutoff values that were used to define patients as hypertensive (4, 6, 7, 8, 9, 10). In the present study, 52% of patients with acromegaly were defined as hypertensive by the current criteria (35), confirming that this condition is much more prevalent in acromegaly than in the general population (10).

We demonstrated an effect of the CYP11B2 –344T/C polymorphism on the risk of hypertension in patients with acromegaly. We observed a 4-fold increased risk of hypertension in patients with the CC genotype compared with patients with other genotypes. This effect is independent of confounding factors such as sex, age, and BMI. Furthermore, the patients with the CC genotype displayed a SBP 10 mm Hg higher compared with patients with the TT/TC genotype, despite that a significantly higher percentage of these patients were on antihypertensive medication (73.1%) than patients with the other genotypes (38.2%). This finding decreases the possibility that current antihypertensive treatment may have acted as a confounding factor and strengthens the significance of the effect of the CYP11B2 –344T/C polymorphism on BP.

We argue that a polymorphism affecting the transcription rate of aldosterone may sensitize the RAAS to a putative stimulatory action of GH at the adrenal level (17, 41), thus explaining the association between the increase in BP with the CYP11B2 –344CC genotype. It is likely that the effect of the polymorphism on transcription is not direct but due to a variant in linkage disequilibrium that acts on the aldosterone synthase transcription rate; in fact, the transcription factor steroidogenic factor-1 that binds to the –344 region does not regulate CYP11B2 (42). A limitation of the present study is the lack of a potential intermediate phenotype because we did not measure plasma renin activity and aldosterone.

In conclusion, we have shown an association of the –344T/C CYP11B2 gene polymorphism to the risk of hypertension and BP in patients affected by acromegaly. These findings point toward an involvement of the RAAS in the pathogenesis of hypertension in acromegaly. This genotype may confer an increased susceptibility to develop hypertension in patients exposed to a chronic excess of GH and IGF-I. Additional prospective studies are necessary to better characterize the role of this polymorphism on intermediate phenotypes and BP in acromegalic patients.


   Acknowledgments
 
We are indebted to Dr. Corrado Magnani, Professor of Medical Statistics, University of Eastern Piedmont, Novara, Italy, for helpful advice on the statistical tests performed in this study.


   Footnotes
 
Disclosure statement: P.Mu., F.V., P.Ma., M.B., S.B., F.D., G.L., A.A., C.C., C.M., E.C.d.U., and M.T. have nothing to declare.

First Published Online September 26, 2006

Abbreviations: BMI, Body mass index; BP, blood pressure; CI, confidence interval; DBP, diastolic BP; RAAS, renin-angiotensin-aldosterone system; SBP, systolic BP.

Received January 10, 2006.

Accepted September 15, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals