(Hypertension. 1997;29:628-633.)
© 1997 American Heart Association, Inc.
Articles |
The Angiotensinogen T235 Variant and the Use of Antihypertensive Drugs in a Population-Based Cohort
the Klinik und Poliklinik fur Innere Medizin II, University of Regensburg (H.S., G.A.J.R.); Institut fur Epidemiologie und Sozialmedizin, University of Munster (H.-W.H., U.K.); GSF Forschungszentrum, Institut fur Epidemiologie, Munich-Neuherberg (J.S.) (Germany); and Laboratoire Biologie Moleculaire, Hopital Broussais, and Institut National de la Sante et de la Recherche Medicale (INSERM) Unit 36, College de France, Paris (A.G.-R., X.J.).
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Abstract |
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Variants of the angiotensinogen gene may increase the risk of developing arterial hypertension, but their effect on the use of antihypertensive medication in the general population remains unclear. Thus, we determined T174M and M235T allele status and angiotensinogen plasma levels in a cross-sectional sample of 634 middle-aged subjects (48.4% men) from the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg cohort study. We found no association between T174M allele status and angiotensinogen levels, blood pressure, or use of antihypertensive drugs. In contrast, multivariate analysis revealed that individuals who carried at least one copy of the T235 allele (n=418) had higher systolic and diastolic pressures (P=.007 and .008, respectively) and were more likely to use an antihypertensive drug (1.6-fold risk, P=.04) than homozygotes for the M235 allele (n=216). The likelihood of taking two or more antihypertensive medications was 2.1-fold higher in carriers of the T235 allele (P=.02). Overall, 22.5% of all antihypertensive drugs taken appeared to be attributable to the excess risk associated with this allele. These associations were replicated in two previous surveys carried out on the same individuals over 10 years. Furthermore, the T235 allele was related to higher angiotensinogen plasma levels [15.5±0.31 versus 16.5±0.15 (nmol/L)/L in homozygotes for the M235 and T235 alleles, respectively; P<.01], which were also related to systolic pressure (P=.03) and more intensive antihypertensive medication (P=.03). We conclude that the angiotensinogen T235 allele accounts for a substantial proportion of antihypertensive drug use in this middle-aged, population-based group of white subjects.
Key Words: hypertension, essential • angiotensinogen • genetics • genotype • antihypertensive agents
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Introduction |
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Both environment and genetic background contribute to the development of essential arterial hypertension, the most frequent cardiovascular disorder, affecting about 20% of the adult population. Chronic antihypertensive medication for essential hypertension has the intent of preventing stroke, heart failure, renal failure, or premature death, ie, conditions directly related to long-term elevation of blood pressure (BP).1 2 3 Given the high prevalence of hypertension and the requirement of continuous treatment, antihypertensive drugs rank first in terms of overall use and related healthcare costs in many countries.4 5
A large number of antihypertensive agents are available that lower BP by a variety of molecular mechanisms. Thus, a predominant goal of clinical and experimental research is to specify intermediate phenotypes that refer to the individual etiology of the common diagnosis of essential hypertension. Identification of intermediate phenotypes such as the renin profile6 may allow the implementation of therapeutic regimens that are directed to the underlying causes of BP elevation. However, the variability of quantitative parameters makes such assessment difficult in patients with essential hypertension.
Angiotensinogen, the specific substrate of the renin-angiotensin system, has been related to essential hypertension in a number of molecular genetic association and linkage studies.7 8 9 10 11 12 13 14 15 16 17 18 Significant linkage was initially demonstrated in a large number of Paris and Utah sibpairs7 and was further confirmed in Caucasian and Afro-Caribbean hypertensive families.12 14 Among different missense mutations at the angiotensinogen gene locus, the common change of methionine to threonine at residue 235 of mature angiotensinogen (M235T) has been associated with hypertension,7 11 13 15 16 17 with a 10% to 30% increase of plasma angiotensinogen.7 11 These studies encouraged us to examine the potential of the M235T change to represent a genetic marker related to BP levels and subsequent use of antihypertensive medication in the general population.
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Methods |
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Study Population
Subjects in this study had initially participated in the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg cohort baseline survey of 1984-85 and its follow-up examination during 1987-88.5 19 Subjects originated from a sex- and age-stratified random sample of all German residents of the Augsburg study area. In 1994, a second follow-up examination including electrocardiographic, biochemical, and anthropometric measurements was offered to 1010 men and women, aged 52 to 65 years, of whom 646 (64%) attended.
All subjects responded to a questionnaire on medical history, physical activities, medication, and personal habits. The information on drugs and estrogen replacement therapy was verified by inspection of prescription forms or medications brought to the MONICA center. Participants who were unable to provide the information at the center were contacted by telephone for precise names and dosages of their current medications. Body height and weight were recorded with subjects in light clothing, and body mass index was computed as weight (kilogram) divided by height (meters squared). Resting BP was measured after subjects had been in a sitting position for at least 30 minutes. BP was read three times from the right arm by two investigators using a mercury sphygmomanometer. The mean of three measurements was used for this study. Hypertension was defined as BP above 140 mm Hg systolic and/or 90 mm Hg diastolic and/or chronic use of antihypertensive agents. Drugs were considered to be used for treatment of hypertension when subjects were aware of hypertension and used antihypertensively active drugs, ie, diuretics, ß-blockers, calcium channel blockers, 
-blockers, centrally acting antihypertensives, and/or angiotensin-converting enzyme inhibitors. Antihypertensive combination therapy was considered when drugs acting through different BP-lowering mechanisms, eg, diuretics and angiotensin-converting enzyme inhibitors, were taken either as separate pills or in a fixed combination.
Biochemical Measurements
Blood was drawn from nonfasting subjects who were in a supine resting position for at least 30 minutes. Determinations of angiotensinogen were made in duplicate. Ten microliters of plasma and 50 ng recombinant human renin (a generous gift of Dr Fischli, Hoffmann–La Roche) were used to generate angiotensin I as previously described.20 Angiotensin I was measured by standard radioimmunoassay (Peninsula Laboratories).
Genotyping
After DNA purification from peripheral blood with the use of a standard protocol, 80 ng genomic DNA was subjected to 30 rounds of specific amplification of exon 2 of the angiotensinogen gene in 20 µL of a buffer that contained 50 mmol/L KCl, 5 mmol/L Tris-HCl, 0.01% gelatin, 1.5 mmol/L MgCl2, 125 µmol/L NTPs, 10 pmol 5'-GTT AAT AAC CAC CTT TCA CCC TT and 3'-primer GCC AGC AGA GAG GTT TGC CT, and 0.5 U Taq polymerase at 94°C for 1 minute, 65°C for 1 minute, and 72°C for 1 minute. The M235T and T174M polymorphisms of the angiotensinogen gene were determined by the allele-specific oligonucleotide hybridization technique, as previously described.7 Determinations of M235T allele status were successfully performed in 634 of the subjects. Because of a shortage of DNA, T174M genotyping could be completed in only 425 subjects.
Statistics
Anthropometric data of subjects with or without the M174 and T235 alleles were compared by t tests for comparison of independent samples or 
2 tests for comparison of classified values. We further analyzed the relation between daily intake of antihypertensive drugs (yes versus no; and no or one drug versus two or more drugs) and the M174 and T235 alleles using a logistic regression, controlling for sex, age, body mass index, and heart rate, to estimate the adjusted relative risks of antihypertensive drug therapy associated with the T235 allele. The proportion of antihypertensive drug use attributable to the M174 and T235 alleles was assessed as suggested by Miettinen.21 Values measured for plasma angiotensinogen were non-normally distributed and slightly skewed to the right. Correlation analyses used logarithmically transformed angiotensinogen values. The relation with covariate-adjusted mean BP values or antihypertensive treatment status was assessed with angiotensinogen as a categorized variable (below and above the 80th percentile). Estrogen replacement therapy, used by about 30% of women, almost all of whom were postmenopausal, resulted in a well-documented elevation of plasma angiotensinogen,22 23 a suppression of radioimmunometrically measured renin,23 and no significant alteration of BP (data not shown22 23 ). To exclude this profound exogenous alteration of plasma angiotensinogen from subsequent analysis, women replacing estrogen were not included in statistical analyses involving this parameter. Probability (P) values are reported for each test and statistical model.
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Results |
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The alleles of the M235T (MM, n=216; MT, n=308; TT, n=110; M allele, 0.59; T allele, 0.41) and T174M (MM, n=13; MT, n=91; TT, n=321; M allele, 0.13; T allele, 0.87) polymorphisms were in Hardy-Weinberg equilibrium and found at a frequency similar to that observed in other white populations.7 17 Anthropometric data of the cohort, which have been previously reported,24 are shown in Table 1
according to their M235T genotype status. Subjects heterozygous or homozygous for the T235 allele presented with similar systolic (149.1±1.1 and 148.6±1.1 mm Hg, respectively) and diastolic (91.9±0.6 and 91.6±0.8 mm Hg) BPs as well as a similar frequency of antihypertensive drug intake (25.3% and 24.5%), such that all carriers of the T235 allele were pooled for further analysis.
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Angiotensinogen M235T Allele Status and Antihypertensive Medication
Individuals that carried one or two copies of the T235 allele were more likely to be taking at least one antihypertensive drug than those homozygous for the M235 allele (Table 1
). Likewise, the number of subjects taking two or more different antihypertensive drugs was significantly higher for those carrying the T235 allele (Table 1). Similarly, the average number of antihypertensive drugs taken by carriers of the T235 allele (0.39 antihypertensive drug per individual) was higher than in those carrying the M235 allele (0.25, P=.02). Despite more antihypertensive drugs taken, subjects that carried one or two copies of the T235 allele displayed higher systolic and diastolic BPs (Table 1) and were at increased risk to present hypertensive BP readings compared with those homozygous for the M235 allele (2 test, P=.03).
Multivariate Tests
The main observation that the T235 variant of the angiotensinogen gene is related to antihypertensive drug therapy was confirmed in multivariate logistic regression analyses. The increase in the probability of antihypertensive drug use associated with the T235 allele was similar to that of an age increase of 5 years or a body mass index higher by 4 kg/m2 (Table 2). After adjustment, 22.5% of all antihypertensive drugs taken by this population were attributable to the excess risk related to the T235 allele. In addition, multivariate linear regression analyses revealed that the increase in systolic BP related to the T235 allele (4.3 mm Hg; confidence interval, 1.2-7.5; P=.007) was comparable to that associated with 10 years of age (4.6 mm Hg, P=.02) or 4 kg/m2 body mass index (4.8 mm Hg, P=.001). Likewise, the T235 allele was associated with an independent increase of diastolic BP (2.3 mm Hg; confidence interval, 0.5-4.0; P=.008).
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Retrospective Analysis
In 1984 and 1987, treatment history had been obtained in the same individuals.5 Thus, we were able to investigate retrospectively whether the association between M235T allele status and antihypertensive medication was consistent over this time period. The data, displayed in Fig 1, confirm a significant association between the T235 allele and antihypertensive medication in both previous surveys.
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Plasma Angiotensinogen
After exclusion of women taking estrogen replacement, plasma angiotensinogen levels were significantly related to M235T allele status (Fig 2). Furthermore, plasma angiotensinogen levels were significantly related to systolic (r=.09, P=.03) but not diastolic (r=.02, P=NS) BP. After adjustment for covariates, subjects with angiotensinogen levels above the 80th percentile [
20 (nmol/L)/L] were more likely to receive two or more antihypertensive drugs (16.7% versus 9.7%; 2 test, P=.04) than the remainder of the cohort.
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Angiotensinogen T174M Allele Status and Hypertension
In contrast to the consistent associations between the 235T allele and hypertension-related phenotypes, we did not detect such associations between the T174M polymorphism and BP, use of antihypertensive medication, or serum angiotensinogen levels in univariate (Table 3) or multivariate (data not shown) analyses. The T174M and M235T polymorphisms were in complete linkage disequilibrium with the 174M allele, only occurring with the 235T allele. Further analysis did not reveal any specific haplotype associated with hypertension-related phenotypes beyond the risk associated with the 235T allele.
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Discussion |
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The angiotensinogen T235 allele has been related to elevated BP in Caucasian, African American, and selected Japanese populations,7 11 13 15 16 17 suggesting that it may serve as a global risk factor for arterial hypertension. Furthermore, the angiotensinogen T235 allele has been associated with higher circulating levels of the respective protein,7 11 a rate-limiting factor for angiotensin II generation25 that has been positively related to BP as well.8 9 10 11 The present investigation confirms these observations in a large population-based sample of middle-aged subjects of Caucasian origin. An even more intriguing finding obtained in this study is that the requirement for and use of antihypertensive medication may partly be the consequence of this genetic predisposition. In particular, subjects who carried one or two copies of the angiotensinogen T235 allele presented with higher BP levels even though they used antihypertensive medication more frequently.
Several limitations apply to the present study. First, the present investigation did not have the power to detect statistical differences between the relatively small numbers of homozygotes for the T235 allele and homozygotes for the M235 allele. Such differences were evident, however, when the larger group of heterozygotes (MT235, data not shown) or all carriers of the T235 allele were compared with homozygotes for the M235 allele. Nevertheless, further studies should reexamine these relationships and determine whether the T235 allele is associated with a dominant or codominant effect on BP levels and use of antihypertensive medication.
Furthermore, a population-based survey such as the present one may be biased by confounding factors that were left unrecognized in the multivariate analysis. Specifically, the use of antihypertensive drugs is certainly affected by the implementation of guidelines for hypertensive therapy. All subjects of the present survey had already participated twice in similar examinations, and thus, most with severe hypertension were aware of their condition and received antihypertensive medication. Furthermore, the response rate in a follow-up examination may be higher in subjects with treated hypertension. However, interestingly, the association between the angiotensinogen T235 genotype and antihypertensive medication was also found at both earlier surveys on these individuals. In fact, in both previous surveys, the differences between genotype groups were even more pronounced, suggesting that the risk for the need for antihypertensive medication in association with the angiotensinogen T235 genotype is particularly strong at a younger age. This finding is in agreement with data reported by Schmidt and coworkers,13 who observed that the T235 allele is specifically a risk factor for hypertension in individuals younger than 50 years of age. Although other unrecognized confounders may have interfered, within the present study group, the association between the T235 genotype and antihypertensive medication was highly consistent and confirmed on three occasions over 10 years.
This study might also be criticized for using the requirement of antihypertensive medication as a (rather artifactual) end point. However, previous population-based surveys revealed that subjects fulfilling this criterion present with the highest risk for hypertension-related end-organ damage or complications such as myocardial infarction, stroke, and premature death.26 27 Thus, a genetic factor associated with an increased risk for entering this particular group may be of substantial significance for both clinical medicine and public health. Therefore, it may be interesting that the angiotensinogen T235 variant has also been documented to be associated with an increased risk of experiencing myocardial infarction.28
Another potential limitation of the present study is that adjustment for dosage or the strength of antihypertensive compounds was not feasible. However, apparently, the T235 allele was particularly associated with the risk of having to take two or more antihypertensive drugs to achieve adequate BP control. A similar observation was made by Tiret et al,17 who studied individuals recruited from electoral rolls in France and general practitioners in Northern Ireland. These authors observed that individuals homozygous or heterozygous for the T235 allele required antihypertensive combination therapy about twice as often as those homozygous for the M235 allele.17 Prospective studies should reassess these observations using defined therapeutic regimens.
Finally, our study, like other cross-sectional studies before, falls short in clarifying the mechanisms that may account for molecular genetic associations. In this regard, the need for caution is implied by studies suggesting that the angiotensinogen gene locus but not specifically the T235 allele is linked to hypertension.12 14 18 The present positive correlations between the T235 allele and plasma angiotensinogen and between plasma angiotensinogen and BP levels seem to be consistent with the notion that increased expression of angiotensinogen itself, either in the liver or in other BP-regulating tissues,20 may correspond to the molecular genetic association.7 Likewise, a direct link between plasma angiotensinogen and BP was demonstrated in transgenic mice bearing two additional copies of the gene.29 Also in agreement with this hypothesis are the findings regarding the T174M variant of the angiotensinogen gene that has so far not been associated with altered angiotensinogen protein levels. Even though some previous association studies suggested a relation between this polymorphism and BP,18 30 we found that the 174M allele was associated with neither angiotensinogen levels nor BP or antihypertensive medication. Nevertheless, positive or negative correlations in molecular association studies do not prove or disprove significant relationships found in other cohorts.
It also should be mentioned that the relative effects of the T235 allele on plasma angiotensinogen and BP seem to be less pronounced than the (presumably subsequent) increased use of antihypertensive drugs. Thus, the present data are also consistent with the hypothesis that some subjects who carry the T235 allele develop a form of hypertension that is manifested at an earlier age and more resistant to nonmedical or single-drug antihypertensive therapy, resulting in more frequent use of antihypertensive combination therapy. In this regard, Dudley and coworkers31 reported data suggesting that patients with arterial hypertension carrying the T235 allele display an impaired response to various antihypertensive drugs.
Irrespective of what the mechanism may be that accounts for the association between the T235 allele and an excess risk of taking one or more antihypertensive drugs, the present study raises the important question of whether subjects presenting with this allele and hypertension (two thirds of all hypertensive individuals in a white population) may benefit specifically from antihypertensive strategies that interact with the renin-angiotensin system. Thus, the T235 allele of the angiotensinogen gene should be tested for its clinical usefulness as a genetic marker of essential hypertension and guide for its therapy.
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG Schu 617/9-1 and 10-1), the Bundesministerium fur Forschung und Technologie (H.S., H.W.H.), a Contract de Recherche Clinique AP-HP (No. 931 007, X.J.) and the Concerted Action of the European Community: Molecular Genetics of Hypertension (No. CT 94153; H.S., X.J.). The authors wish to thank the 646 men and women who participated in this MONICA survey for the third time. Furthermore, we wish to thank Susanne Kurzinger for excellent technical support.
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Footnotes |
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Reprint requests to PD Dr H Schunkert, Klinik und Poliklinik fur Innere Medizin II, University of Regensburg, D-93042 Regensburg, FRG.
Received June 13, 1996;
first decision July 8, 1996;
first decision September 12, 1996;
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