(Hypertension. 1995;25:688-693.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensinogen Gene and Blood Pressure in the Japanese Population
From the 1st Dept of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city, Shiga-ken, Japan.
Correspondence to Naoharu Iwai, MD, 1st Dept of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city 520-21, Shiga-ken, Japan.
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Abstract |
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Abstract A molecular variant of the angiotensinogen gene with threonine instead of methionine at position 235 (ie, with M235T polymorphism) has been shown to be associated with essential hypertension in Caucasian populations. The purpose of the present study was to assess whether the M235T polymorphism was associated with essential hypertension in the Japanese population. The study population consisted of 347 subjects selected in our outpatient clinic. The clinical data included in the analyses were sex, age, body mass index, cholesterol level, genotype of the angiotensinogen gene, genotype of the angiotensin-converting enzyme gene, and systolic and diastolic blood pressure. Multiple regression analysis revealed that only body mass index was a predictor of both diastolic and systolic blood pressure in these 347 subjects, but the genotype of the angiotensinogen gene was identified as a predictor of both diastolic and systolic blood pressure in a subpopulation less than 50 years of age. However, in a subpopulation more than 50 years of age, body mass index was the only predictor of both systolic and diastolic blood pressure. Of the 347 subjects, 189 had a technically excellent echocardiogram at the initial observation period. Multiple regression analysis revealed that sex, body mass index, diastolic blood pressure, and genotype of the angiotensin-converting enzyme gene were predictors of left ventricular mass. Although subjects with the TT angiotensinogen genotype had significantly greater left ventricular mass than those with either the TM or the MM genotype, the effects of the genotype of the angiotensinogen gene on left ventricular mass were mainly due to effects on blood pressure.
Key Words: angiotensinogen • angiotensin-converting enzyme • hypertension, genetic • genes
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Introduction |
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Hypertension is a multifactorial disease that has both environmental and genetic components. From 20% to 40% of the blood pressure variation in the general population can be attributed to genetic factors.1 By identifying major genetic factors, we may be able to provide a more reasonable therapeutic approach to this major public health problem.
Genes encoding components of the renin-angiotensin system are attractive candidates for the genetic basis of cardiovascular diseases. Recently, molecular variants of the human angiotensinogen gene have been reported to be associated with essential hypertension in Caucasian populations.2 Fifteen point mutations in the angiotensinogen gene have been identified, two of which were associated with essential hypertension by sibling-pair analysis: one with threonine instead of methionine at position 235 and one with methionine instead of threonine at position 174. Moreover, the plasma angiotensinogen concentration was higher in subjects with the TT genotype at position 235 than in subjects with either the TM or the MM genotype.
In the investigation of polygenic disorders such as hypertension, the genetic or ethnic background of the study population is very important. In humans, for example, many studies have confirmed ethnic differences in ambulatory blood pressure.3 4 Genetic differences are also seen in the rat; although the renin gene locus was reported to be associated with high blood pressure in an F2 population derived from spontaneously hypertensive and Lewis rats,5 this locus was not associated with high blood pressure in an F2 population derived from stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.6
In the present study, we investigated whether a molecular variant of the angiotensinogen gene at position 235 was associated with hypertension in the Japanese population. The possible association of this genetic polymorphism with left ventricular hypertrophy (LVH) was also investigated.
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Methods |
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Study Population
The study population was drawn from 650 subjects selected by four staff doctors in our outpatient clinic from April 1992 to May 1994. Because our department mainly treats patients with cardiovascular diseases, almost all subjects who visited our outpatient clinic had symptoms or signs suspected to be related to such these diseases, such as ischemic heart disease, hypertension, arrhythmia, valvular disease, cardiomyopathy, and cerebrovascular diseases. All subjects who agreed to supply peripheral blood for DNA analysis for studies on the genetic basis of cardiovascular diseases were included (informed consent was given). Subjects with myocardial infarction, a history of symptomatic congestive heart failure, hypertrophic or idiopathic dilated cardiomyopathy, valvular diseases, congenital heart disease, unstable angina pectoris, or serious arrhythmia were excluded from the present study. Subjects with hypertension, angina pectoris, or arrhythmia who had been treated at the first visit of our outpatient clinic were also excluded, because their precise clinical data before treatment were not available. Subjects for whom the cause of hypertension was known and those with reduced renal function with a serum creatinine level above 1.5 mg/dL were also excluded. The clinical data considered in the analyses were sex, age, body mass index, cholesterol level, index of left ventricular hypertrophy on electrocardiogram (ECG-LVH), systolic blood pressure (SBP), and diastolic blood pressure (DBP). The mean value of the blood pressure on two or more separate occasions at the initial observation period (while the patient was taking no medication) in our outpatient clinic was used as each patient's blood pressure value. Subjects whose blood pressure was measured only once were also excluded from the present study. Of 650 subjects, 347 met the criteria described above. Of these 347 subjects, 189 had a technically excellent echocardiogram either while taking no medication or within 2 weeks after the initiation of any kind of medication. Of these 347 subjects, 142 were diagnosed as having no cardiovascular disease and as having SBP and DBP less than 160 and 90 mm Hg, respectively.
Left ventricular mass (LVM) was calculated from M-mode echocardiographic measurements of the left ventricle using an SSH160A system with 3.75-MHz transducers (Toshiba). Two-dimensionally guided M-mode measurements of left ventricular end-diastolic dimension (LVDd), end-diastolic interventricular septum thickness (IVS), and end-diastolic posterior wall thickness (LVPW) were performed at the left ventricular minor axis at the level of the chordae tendinae just beyond the mitral leaflet tips, as recommended by the American Society of Echocardiography.7 Each measurement was taken three times, and the average value was used to calculate LVM (in grams) according to the formula of Devereux and Reichek8 :
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We corrected LVM by dividing it by height (in centimeters), as previously recommended.9 All echocardiograms were performed by three experienced echocardiographers and recorded on videotape. The quality of the echocardiograms was verified by experts in echocardiography.
ECG-LVH was diagnosed according to the point score system of Marquette Electronics, Inc. This system includes five categories for ECG-LVH: normal, minimal voltage criteria for LVH, moderate voltage criteria for LVH, voltage criteria for LVH, and LVH. In the present study, minimal voltage criteria for LVH and moderate voltage criteria for LVH were classified as borderline, and voltage criteria for LVH and LVH were classified as LVH.
Determination of Angiotensinogen and Angiotensin-Converting Enzyme
Genotypes
High–molecular weight DNA was isolated from peripheral
leukocytes, as previously described.10 The exon 2 region,
which covers the M235T polymorphic site of the angiotensinogen gene,
was amplified by polymerase chain reaction, with
5'-GAGTCGCACAAGGTCCTGTC-3' (sense) and 5'-GCCAGCAGAGAGGTTTGCCT-3'
(antisense) used as primers. About 100 ng genomic DNA was amplified in
a total volume of 25 µL containing 50 mmol/L KCl, 5 mmol/L Tris-Cl,
0.01% gelatin, 2.5 mmol/L MgCl2, 0.2 mmol/L of each
deoxynucleotide triphosphate, 20 pmol of each primer, and 0.5 U
Taq DNA polymerase (Perkin-Elmer Cetus). After an initial
denaturation step (1 minute at 95°C), each of the 35 cycles consisted
of 1 minute at 95°C, 1 minute at 58°C, and 2 minutes at 74°C. To
determine the M235T genotype, the amplified polymerase chain reaction
product was electrophoresed on 1.4% agarose gel and then blotted onto
a nylon membrane (Hybond N+). Two duplicate filters were prepared.
Allele-specific oligonucleotide hybridization was performed according
to the method described by Ward et al.11 In brief, one of
the duplicate filters was hybridized with an oligonucleotide probe and
end labeled with 32P, corresponding to M235
(5'-GCTCCCTGACGGGAGCC-3'), and the other filter was hybridized with a
probe corresponding to T235 (5'-GGCTCCCATCAGGGAGC-3'). After
hybridization in 7% polyethylene glycol, 10% SDS, and 50 mmol/L
sodium phosphate (pH 7.0) overnight at 37°C, the filters were washed
in 6x SSC for 20 minutes at room temperature and then washed again for
20 minutes at 48°C.
The genotype of the angiotensin-converting enzyme (ACE) gene was determined by use of the polymerase chain reaction according to the method described by Rigat et al.12 The sense oligonucleotide primer was 5'-CTGGAGACCACTCCCATCCTTTCT-3', and the antisense primer was 5'-GATGTGGCCATCACATTCGTCAGAT-3'. These primers enabled us to detect a 490-bp genomic DNA segment corresponding to the insertion allele as well as a 190-bp segment corresponding to the deletion allele. Reactions were performed in a final volume of 25 µL containing 10 pmol of each primer, 2.5 mmol/L MgCl2, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.4), 0.1 mg/mL gelatin, 0.2 mmol/L of each deoxynucleotide triphosphate, and 0.5 U TaqDNA polymerase (Toyobo). The amplification profile included an initial denaturation at 94°C for 60 seconds and 35 cycles of denaturation at 94°C for 60 seconds, annealing at 58°C for 60 seconds, and extension at 74°C for 120 seconds. The polymerase chain reaction products were resolved in 1.5% agarose gels and visualized with ethidium bromide staining. Reagents not specifically indicated were all purchased from Nakarai Tesque Inc.
Statistical Analyses
All statistical analyses were conducted using the
SAS statistical package licensed to Kyoto University (site
0002436001). Summary data are expressed as mean±SD. A backward
selection procedure of a multiple regression analysis was used to
identify important predictors of SBP, DBP, and LVM. A P
value of 10% or larger was the criterion for removing a variable in
constructing a clinical model. One-way ANOVA and
2 analyses were used to compare differences
among subjects with different genotypes.
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Results |
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Effects of Genotypes of the Angiotensinogen Genes on Blood Pressure
The Figure shows a typical example of genotyping of M235T polymorphism of the angiotensinogen gene. The validity of our detection method was confirmed by direct sequencing of the amplified DNA from several subjects.
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The characteristics of the study population are summarized in Table 1 according to the M235T genotype of the angiotensinogen gene. The study population consisted of 347 subjects 19 to 82 years old. No significant differences in the female-male ratio, frequency of the genotype of the ACE gene, frequency of ECG-LVH, age, body mass index, cholesterol level, SBP, or DBP were observed among subjects with different genotypes of the angiotensinogen gene. A backward elimination procedure, in which sex (male scored as 0, female as 1), genotype of the ACE gene (II+ID scored as 0, DD as 1), genotype of the angiotensinogen gene (TT scored as 0, TM+MM as 1), age, body mass index, and cholesterol were considered independent variables, revealed that only body mass index was a predictor of both SBP and DBP (Table 2). However, the inclusion of elderly subjects in the study population may have obscured the genetic factors in hypertension.
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Of the 347 subjects, 219 were less than 60 years of age. The characteristics of this subpopulation are shown in Table 3. SBP and DBP were significantly higher in subjects with the TT genotype of the angiotensinogen gene than in subjects with either the TM or the MM genotype. A significantly higher frequency of ECG-LVH was also observed in subjects with the TT genotype. Backward elimination procedures, in which sex, genotype of the ACE gene, genotype of the angiotensinogen gene, age, body mass index, and cholesterol were considered independent variables, revealed that body mass index (P=.0062 for SBP and P=.0423 for DBP) and the genotype of the angiotensinogen gene (P=.0300 for SBP and P=.0442 for DBP) were predictors of both SBP (R2=.054, P=.024) and DBP (R2=.037, P=.017). The genotype of the ACE gene was not a predictor of blood pressure in this population. This analysis in these younger subjects suggests that the effects of the genotype of the angiotensinogen gene may be more evident at a younger age. Similar backward elimination procedures of blood pressure in even younger subjects (less than 50 years old; Table 4) revealed that the genotype of the angiotensinogen gene was a predictor of both SBP and DBP (Table 5). Blood pressure in this younger population was 155±27/93±15 mm Hg in the 83 TT subjects, 139±27/86±16 mm Hg in the 34 TM subjects, and 135±33/84±13 mm Hg in the 5 MM subjects (P=.0135 for SBP and P=.0372 for DBP by one-way ANOVA). However, in subjects more than 50 years of age (Table 6), the genotype of the angiotensinogen gene was not a predictor of blood pressure. Only body mass index was a predictor of DBP, and body mass index, cholesterol level, and age were predictors of SBP (Table 7).
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In a population less than 65 years of age (291 subjects), SBP and DBP were predicted by body mass index (SBP, P=.0001; DBP, P=.0002) and the genotype of the angiotensinogen gene (SBP, P=.057; DBP, P=.100) (SBP, R2=.059, P=.0001; DBP, R2=.053, P=.0004). The genotype of the angiotensinogen gene had only marginal effects on blood pressure in this population. However, in a population less than 45 years of age (76 subjects), only the genotype of the angiotensinogen gene was a predictor of blood pressure. Blood pressure in this population was 153±24/93±12 mm Hg in the 46 TT subjects, 139±28/85±16 mm Hg in the 27 TM subjects, and 120±19/79±10 mm Hg in the 3 MM subjects (P=.0129 for SBP and P=.0382 for DBP by one-way ANOVA).
Effects of Genotypes of the Angiotensinogen and ACE Genes on
LVM
Of 347 subjects, 189 had a technically excellent echocardiogram at
the initial observation period (while taking no medication) or within 2
weeks after the initiation of any kind of medication. The
characteristics of these 189 subjects are summarized in Table 8 according to the genotype of the angiotensinogen gene.
No significant differences in the frequency of the genotype of the ACE
gene, age, body mass index, or cholesterol were observed among patients
with different genotypes of the angiotensinogen gene. However, DBP,
LVM, and LVM/height were significantly higher in subjects with the TT
genotype of the angiotensinogen gene than in those with the TM or the
MM genotype (Table 8). A backward elimination procedure, in which sex,
genotype of the ACE gene, genotype of the angiotensinogen gene, age,
body mass index, cholesterol, SBP, and DBP were considered independent
variables, revealed that the genotype of the ACE gene, sex, age, body
mass index, and DBP were predictors of LVM (Table 9).
LVM tended to be slightly higher in subjects with the TT genotype of
the angiotensinogen gene than in subjects with either the TM or the MM
genotype (P=.0922). Because some of these 189 subjects were
elderly, the genetic factors in the development of LVH might have been
obscured; therefore, subjects more than 60 years of age were excluded
and predictors of LVM reassessed. A multiple regression analysis of
data from the 115 subjects less than 60 years of age revealed that
52.3% of the total variance in LVM could be explained
(P=.0001) by the genotype of the ACE gene
(P=.0024, coefficient=32.552), sex (P=.0001,
coefficient=-38.459 [male=0, female=1]), age (P=.0233,
coefficient=1.17), body mass index (P=.0001,
coefficient=4.898), DBP (P=.0001, coefficient=1.491), and
genotype of the angiotensinogen gene (P=.2239,
coefficient=-11.033 [TT=0, TM+MM=1]). The genotype of the
angiotensinogen gene appeared to have no significant effects on LVM in
this younger subpopulation. In these 115 subjects, those with the TT
genotype tended to have a higher DBP than those with either the TM or
the MM genotype (90±16 mm Hg versus 84±14 mm Hg, P=.062
by one-way ANOVA).
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Discussion |
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Angiotensinogen Gene and Blood Pressure
Hypertension is a multifactorial disease that has both environmental and genetic components. Age, sex, and body mass index are especially important factors in determining blood pressure levels in the general population.13 14 Because our study population consisted of hospital subjects, which tended to make the frequency of hypertension higher among both female and male subjects, sex was not identified as a predictor of blood pressure in our study population. In addition, perhaps because of the higher frequency of hypertension among our younger subjects, age was also not identified as a predictor of blood pressure. Therefore, it is important to bear in mind that the results described here were obtained in a hospital-based population.
The allele frequency of T235 was higher in our Japanese population (.795, Table 1) than in Caucasian populations (.52 to .36).2 Therefore, we have only 20 subjects with the MM genotype of the angiotensinogen gene (Table 1). Thus, in the present study, subjects with either the TM or the MM genotype were categorized in a single group. A larger number of subjects will be necessary to compare phenotypic differences among subjects with TT, TM, and MM genotypes of the angiotensinogen gene.
As described in "Results," the effects of the genotype of the angiotensinogen gene on blood pressure were not evident in our total population. However, in younger subpopulations that were less than 60, 50, or 45 years of age, the effects of the genotype of the angiotensinogen gene were evident. On the other hand, in an elderly population more than 50 years of age, body mass index was the only predictor for both SBP and DBP. It is generally thought that the effects of a genetic factor are more evident at a younger age, and the effects of environmental factors become evident at an older age. Thus, our result that the genotype of the angiotensinogen gene was the only predictor of blood pressure in subjects under the age of 50 is rather strong evidence that the angiotensinogen gene contributes to essential hypertension in the Japanese population. The hypothesis that the effects of the angiotensinogen gene variant on blood pressure are only evident in younger populations may be in agreement with the concept that the genetic control of SBP and DBP changes continuously with age.15 16
Although we did not determine the plasma levels of angiotensinogen in our study subjects, the TT genotype of the angiotensinogen gene has been reported to be associated with a higher plasma level of angiotensinogen than either the TM or the MM genotype.2 Because the plasma level of angiotensinogen is close to the Km for renin, it is likely that the plasma level of angiotensinogen can influence angiotensin I production in circulating blood and peripheral tissues. However, it is important to keep in mind that statistical tests of association cannot resolve the causal pathways underlying observed associations.
LVM and Genotypes of the Angiotensinogen and ACE Genes
Although the development of LVH depends on blood pressure, the
correlation between LVM and blood pressure is poor.17 18
Recent studies have indicated that the genotype of the ACE gene is a
predictor of LVM.19 20 Because angiotensin II is not only
a vasoactive peptide but also a growth-promoting factor,21
it is also probable that the genotype of the angiotensinogen gene has
some effect on the development of LVH that is independent of its
effects on blood pressure.
In our 189 echocardiographically assessed subjects, DBP, body mass index, genotype of the ACE gene, sex, and age were identified as predictors of LVM. The identification of the ACE genotype as a predictor of LVM is an extension of our previous observation.20 Although the genotype of the angiotensinogen gene appeared to make a slight contribution to LVM in these 189 subjects independent of its effects on blood pressure (Table 9), a similar contribution was not observed in subjects less than 60 years of age. Although the LVM of subjects with the TT genotype was greater than that of subjects with either the TM or the MM genotype (Table 8), this difference was mainly due to the effects of the angiotensinogen genotype on blood pressure.
Inconsistency Among Studies of the Angiotensinogen Gene
There have been several investigations of the association between
the genotype (M235T) of the angiotensinogen gene and blood pressure.
Some, including our preliminary report,22 have indicated
that there is a positive association,2 23 24 but others
have not.25 26 Even in the present study, a positive
association was observed only in a younger subpopulation, and no
significant association was observed in a subpopulation more than 50
years of age. In this latter subpopulation, body mass index was a very
strong predictor of blood pressure. Thus, inconsistency among the
previous studies might be due to differences in the criteria for
subject selection. It is likely that multivariate comparisons, as were
used in the present study, may be more sensitive than univariate
comparisons ignoring confounding variables, as were used in the
previous studies. Differences in genetic or ethnic background may also
play a role. It is generally believed that M235T polymorphism of the
angiotensinogen gene itself does not cause hypertension but is rather a
marker of the DNA segment that actually is responsible for
susceptibility to hypertension.27 The informative value of
this M235T polymorphism may be sensitive to phylogenetic distance and
the heterogeneity of the genetic background.
The present study indicated that the TT genotype of the angiotensinogen gene was a predictor of blood pressure in a subpopulation less than 50 years of age from a total of 347 Japanese subjects. In contrast, body mass index was a strong predictor of blood pressure in a subpopulation more than 50 years of age. Thus, age is a very important factor in the genetic analysis of essential hypertension.
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Acknowledgments |
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This study was supported in part by a grant-in-aid from the Japanese Ministry of Education, Science, and Culture.
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