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(Hypertension. 1997;30:1331-1337.)
© 1997 American Heart Association, Inc.
Articles |
Association Between the Angiotensinogen 235T-Variant and Essential Hypertension in Whites
A Systematic Review and Methodological Appraisal
From the Department of Internal Medicine, Division of Endocrinology and Nephrology, Universitätsklinikum Benjamin Franklin, Free University of Berlin. Dr Kunz is currently affiliated with the Department of Internal Medicine, Division of Nephrology and Transplantation Universitätsklinikum Virchow-Charité, Humboldt-University Berlin, Germany.
Correspondence to Prof Arya M. Sharma, Medizinische Klinik, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Federal Republic of Germany. E-mail sharma{at}zedat.fu-berlin.de
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Abstract |
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Abstract Recently, an allelic variant of the angiotensinogen gene (AGT 235T) has been associated with increased risk of hypertension. However, this finding has not been confirmed by all investigators. A meta-analysis was performed to examine the association between the AGT 235T-allele and hypertension in whites and to identify potential reasons for the controversial results. All relevant articles published between 1992 and 1996 were identified through multiple sources. The studies were methodologically appraised, and the frequency of the AGT 235T-allele was extracted. The 235T-allele frequency was pooled using the common odds ratio (OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day test. Together these studies present data on 5493 patients. The AGT 235T-allele was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29; P<.0001). This association increased in studies with positive family history (OR: 1.42; 95% CI: 1.25 to 1.61, P<.0001), recruitment of cases from referral centers (OR: 1.39; 95% CI: 1.20 to 1.62, P<.0001), and more severe hypertension (OR: 1.34; 95% CI: 1.22 to 1.47, P<.0001). However, the presence of methodological problems in all studies gives rise to serious concerns regarding bias and confounding. Despite a statistically significant, albeit weak, association between the AGT 235T variant and hypertension that has been confirmed through sensitivity analysis, this finding has to be interpreted with caution, as the methodological weaknesses of the individual studies are likely to have biased the outcome of the meta-analysis. Clearly, more rigorous methods need to be applied in association studies on the genetics of human hypertension.
Key Words: angiotensinogen • genetics • meta-analysis • humans
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Introduction |
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Hypertension is a common circulatory disorder of multifactorial origin caused by a combination of genetic and environmental factors. Family studies suggest that genetic factors account for 40% of blood pressure variability across all levels of blood pressure.1 Given the complex interplay of different physiological systems in regulating blood pressure, it is evident that the widely prevalent form of "essential" hypertension is not a singular disease but rather a clinical syndrome attributable to a variety of underlying pathophysiological mechanisms. The recent development of powerful molecular genetic techniques has resulted in a widespread endeavor to dissect the genetic factors accounting for hypertension in various populations.2
Numerous features of hypertension complicate the identification of the underlying molecular mechanisms. These features include late onset of disease, quantitative variability of blood-pressure phenotype, polygenetic inheritance, genetic heterogeneity, incomplete penetrance, unknown mode of inheritance, and the strong but variable effect of environmental factors, including diet, physical activity, and behavioral stress. Therefore, recruitment of families and patients for genetic studies of hypertension requires precise definitions of disease and disease-free status and must also consider exposure to various confounding environmental factors in these subjects.
In 1992, Jeunemaitre et al3 reported linkage of the angiotensinogen-gene locus to hypertension in hypertensive sibling pairs recruited in Salt Lake City and Paris. Subsequent screening of the angiotensinogen gene for molecular variants led to the identification of a missense mutation, resulting in the substitution of a threonine (T) for a methionine (M) at codon 235. Using a case-control approach in which they compared the frequency of this so-called "AGT 235T variant" in hypertensive cases with that in normotensive control subjects, Jeunemaitre et al reported this variant to be more common in hypertensive subjects. Furthermore, the AGT 235T variant was also associated with increased levels of circulating angiotensinogen, indicating that this variant may indeed be of functional significance. A recent study shows that the AGT 235T variant is in tight linkage disequilibrium with a guanine-to-adenosine transition at -6 bp upstream of the initiation site of transcription, which may result in a higher basal transcription rate of this gene.4
Since the initial report,3 several family and sib-pair studies have confirmed linkage of the angiotensinogen gene and hypertension in various populations,5 6 but it has also been shown that marked variations in AGT 235T-allele frequencies occur in the general population of various ethnic groups. While the average frequency for the AGT 235T-allele was between 0.35 and 0.45 among whites,3 7 8 9 10 it increased to 0.6 to 0.75 among Japanese11 12 13 and to rates as high as 0.84 to 0.93 among blacks.6 14 15 However, even within the various ethnic groups, the association between the AGT 235T-variant and hypertension has been inconsistent, with half the studies on whites claiming a positive association3 7 16 17 18 and the other half not detecting a positive effect.5 8 9 10 19 20
The primary objective of this systematic review was, therefore, to examine the reported association between the AGT 235T-variant and hypertension and to explain the controversial results in the published literature. Because the initial report and the majority of studies have examined this relationship in whites, we limited our present review to this ethnic group. This topic is well suited for a meta-analytical approach because all studies postulate the same relationship between hypertension and the 235T-variant of the angiotensinogen gene. Also, all studies have investigated this hypothesis using a similar strategy of comparing allelic or genotypic frequencies in hypertensive cases to those in normotensive control subjects.
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Methods |
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A systematic literature search was performed using MEDLINE, REFERENCE UPDATE, reference lists of all primary studies, abstract volumes, and expert files, and hand-searching of relevant journals on hypertension and human genetics. Experts in the field were also contacted for information regarding additional relevant studies. The MEDLINE search covered October 1992 (publication of the first study) to January 1997 using the following MESH-headings: "angiotensinogen-genetics," "hypertension-genetics," "pressure-genetics," "human," and "adults." REFERENCE UPDATE was searched for articles under the headings "angiotensinogen," "genetics," and "human." All studies that investigated the association between the AGT M235T-variant and essential hypertension in whites were collected. These studies were then examined for their methodological quality as case-control studies with particular attention paid to the possibility of bias in the selection of case and control subjects. The authors of individual studies were contacted for clarification and further information when necessary. The study populations were then examined on the basis of the following criteria: definition of phenotype, age at onset, family history of hypertension, and severity of disease. Confounding risk factors for hypertension (including age, sex, body mass index, smoking, and alcohol consumption) were identified and tabulated. The allele and genotype frequencies were extracted wherever possible, and the odds ratios (ORs) were calculated.
The common OR estimator (fixed effect model) and the 95% confidence
interval (CI) was calculated using the Mantel-Haenszel
technique.21 Homogeneity was assessed visually and on the
basis of the 
2 test by Breslow-Day22 using a
significance level of P=.05. To assess the influence of
certain risk factors and design features on the estimated strength of
the association, sensitivity analyses were performed on the
basis of the following criteria: family history of hypertension,
severity of hypertension (based on time of onset, 
2 drugs, or as
stated by the authors), body mass index, site of recruitment of case
and control subjects (population-based versus referral centers under
the assumption that patients with more severe or more complicated
disease are referred to specialized centers), and method of DNA
analysis.
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Results |
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General Considerations
A total of 11 studies on 14 populations were identified,3 5 7 8 9 10 16 17 18 19 20 and the results from 5493 patients summarized. While 5 of these studies in 6 populations found a significant association between the AGT M235T-variant and hypertension,3 7 16 17 18 all other studies failed to confirm these findings.5 8 9 10 19 20
Methodological Assessment
Selection of Case and Control Subjects
Hypertensive case subjects were selected from one of the following
sampling frames (Table 1
): general
population, primary care centers, or
self-referral3 5 7 8 9 10 17 19 20 or special hypertension
referral centers.3 5 7 16 18 In 9 of the 11 studies,
selection of cases was based on predefined
criteria.3 5 7 8 9 10 16 18 19 The remaining 2 studies used
convenience samples at hand consisting of subjects initially recruited
for reasons other than hypertension.17 20 Normotensive
control subjects were selected from a variety of places: special
registers of healthy families,3 blood
donors,7 16 spouses,7 primary care
clinics,5 10 18 the general
population,9 17 19 20 self-referral,8 or
previous studies.3 One study specified neither the
selection process nor criteria for the control group.5
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Definition of Hypertension
The definition of hypertension varied widely among the studies
(Table 1
). Two studies7 9 included mild hypertension
defined according to World Health Organization criteria: blood pressure
levels >140/90 mm Hg. One study17 included patients
with isolated systolic hypertension (>160/90 mm Hg). The
threshold of the diastolic blood pressure as an inclusion
criterion ranged from 90 mm Hg,18 95
mm Hg,3 5 7 16 and 100 mm Hg20 to
105 mm Hg.19 Current drug treatment for
hypertension or treatment before a certain age was frequently used as a
surrogate or additional criterion.3 5 7 8 9 18 20 Three
studies limited themselves to more severe hypertension (160/95
mm Hg17 and diastolic pressure 100
mm Hg20 or higher19 ). In three studies, the
observed blood pressure was not reported separately for hypertensive
and normotensive subjects,3 5 7 which did not allow for a
comparison of the blood pressure between the groups.
Family History
While all studies aimed to identify a potential genetic marker for
hypertension, only six populations in five studies specifically
included family history of hypertension as a selection criterion for
cases,3 5 8 16 18 and only three studies3 5 8
presented the definition for positive family history (Table 2). In one study, family history was
considered after recruitment was completed, and it was then
investigated as a subgroup.7 No information on family
history was available in six populations.9 10 16 17 19 20
Only three studies stated that control subjects were selected on the
basis of a negative family history,8 16 18 and the other
studies did not further describe the selection criteria for control
subjects.
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Matching and Environmental Factors
Formal matching (Table 1) of case and control subjects regarding
important sociodemographic and environmental factors (Table 2) was
performed in eight studies.3 8 9 10 16 17 18 19 Yet, remarkable
differences in body mass index3 18 and age or
sex8 10 remained between cases and controls in four of
these studies. In general, sociodemographic factors diverged
considerably between cases and controls. Cases tended to be older than
controls, with one study allowing a mean difference as large as 18
years.7 One study failed to report either sex distribution
or age of cases and controls separately.5 Obesity among
cases was present in all studies and ranged from mildly overweight
(25.1 kg/m2)17 to heavily overweight (29.7
kg/m2).3 Furthermore, cases tended to be more
obese than controls. Data on other important risk factors like smoking,
lipid status, or salt and alcohol consumption were limited in most
studies.
Method for DNA Analysis
DNA analysis was performed using four different
techniques: allele-specific hybridization,3 16 18 20
restriction analysis,5 8 10 17 19 a mutagenically
separated PCR technique,7 and single-strand conformation
analysis (Table 1).9
Analysis of the Genetic Data
Allele frequency was calculated for all studies (Table 3). Among controls, the mean allele
frequency for the AGT 235T-allele was 0.41 (95% CI:
0.34 to 0.48) among cases, the mean allele frequency for the
AGT 235T-allele increased to 0.45 (95% CI: 0.38 to
0.52). The frequency of the AGT 235T-allele among
controls was within the 95% CI in all but three
studies.5 17 19 The first two studies5 19
reported a higher than expected frequency (both 0.49), whereas the
allele frequency in the third study17 (0.31) was
outside the lower border of the confidence interval.
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The ORs of having hypertension in the presence of the AGT
235T-allele in individual studies are summarized in Table 3 and Fig 1. A statistically significant
association between the AGT 235T-allele and hypertension
was detected in five populations.3 16 17 18 When all studies
were pooled, the overall association became statistically highly
significant (P<.0001), whereby the AGT
235T-allele was associated with a 20% increase in the risk of
having hypertension (OR: 1.20; 95% CI: 1.11 to 1.29). Visual and
statistical inspection for heterogeneity did not detect
significant differences between the studies.
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Sensitivity analyses based on risk factors, design features and
potential confounders were performed to further explore the
relationship and the strength of the associations. When the family
history of hypertension was considered in the selection of cases, the
OR increased to 1.42 (95% CI: 1.25 to 1.61; P<.0001)
(Table 4, top; Fig 2). In contrast, the OR decreased in
studies where the family history had not been elicited (OR: 1.08; 95%
CI: 0.98 to 1.19; P>.05) (Table 4, bottom; Fig 2).
Similarly, when sensitivity analysis was performed according to
severity of hypertension, the OR increased to 1.34 (95% CI: 1.22 to
1.47; P<.0001) in patients with more severe hypertension,
whereas it decreased to 1.15 (95% CI: 1.05 to 1.26; P=.002)
in patients with mild to moderate hypertension. In patients with both
features, positive family history and more severe hypertension, the OR
rose even further to 1.47 (95% CI: 1.28 to 1.68; P<.0001).
In studies in which cases were recruited from referral centers, an OR
of 1.39 (95% CI: 1.20 to 1.62) was observed compared with an OR of
1.11 (95% CI: 1.01 to 1.22) in studies with recruitment of cases from
the general population. Sensitivity analyses on body mass index
or method of genotyping did not show any differences. Due to missing
data on genotype frequency in a large proportion of studies, no
meaningful analysis based on this parameter could
be performed.
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Discussion |
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The primary objective of this study was to evaluate the association between the 235T-variant of the angiotensinogen gene and hypertension in whites on the basis of a systematic review of published association studies. Pooling the results of more than 5000 patients from the individual studies revealed a statistically significant association between the AGT 235T-variant and hypertension. In the overall analysis, the AGT 235T-variant conferred a 20% increased risk of having hypertension. The risk increased further when sensitivity analysis was performed in patients recruited from specialized centers, in patients with a positive family history, or in patients with moderate to severe hypertension, and it was twice as high in patients with both, positive family history and more severe hypertension. Together with the evidence from linkage studies implicating the angiotensinogen locus in hypertension3 5 6 and the clinical findings that the AGT 235T-variant is associated with increased plasma levels of angiotensinogen3 23 24 and antihypertensive drug use,25 the results of our meta-analysis seem to support the hypothesis that the AGT 235T-variant confers an increased risk for the development of hypertension.
However, several limitations apply to the present study: The quality and reliability of a meta-analysis is determined by the quality of the underlying studies,26 and impressive sample sizes might suggest robustness of the results where there is none. Alternatively, the systematic and comprehensive approach of a meta-analysis can be helpful in identifying differences between studies that might explain the conflicting findings. In this regard, it is important to note that the case-control design used to investigate the influence of the AGT 235T-variant is known to be prone to selection bias and confounding especially when applied to the investigation of complex genetic traits. The design of the individual study therefore needs to take into account the multifaceted aspects of the disease.2 However, the current analysis reveals that most studies had deficiencies in the selection, definition, and/or characterization of cases and controls.
Collection of a homogeneous population is improved by selecting appropriate case subjects and, even more importantly, appropriate control subjects by using explicit criteria like a precise definition of hypertension, family history, severity of disease, and age of onset.27 Only four studies restricted their investigations to patients with more severe hypertension,8 17 19 20 whereas some studies also recruited patients with mild hypertension.7 9 Other studies failed to report the blood pressure levels in their control groups.5 7 Data on family history of hypertension were scarce given that all studies investigated the influence of a genetically determined factor on hypertension. Less than half the studies stated a positive family history of hypertension in case subjects as mandatory criteria for inclusion,3 5 8 16 18 and even fewer asked for a negative family history of hypertension for control subjects.8 16 18 Sensitivity analysis suggests that there is more to it than just scarce description of the methods, as studies with more specific selection of cases regarding family history and severity of hypertension detected a stronger association, whereas the effect vanished in studies with broader and less specific inclusion criteria.
Another issue of major importance for association studies investigating the genetics of a complex trait is control for factors like age and blood pressure that may confound the expression of the phenotype in cases and controls.28 In most studies, however, controls tended to be younger and less obese than cases, potentially leading to misclassification. Thus, control subjects might develop hypertension as they grow older or more obese, especially if they also happen to have a positive family history of hypertension. Such misclassification would dilute the true underlying effect of the AGT 235T-allele and thus underestimate any existing association.
Furthermore, allele frequency was used as a surrogate parameter for genotype because the latter was not presented in a sufficient number of studies. Allele frequency is a statistical quantity and its direct translation into a biological effect may be debatable. It neglects the complexity of the pattern of inheritance and the associated heritable risk and cannot distinguish whether the effect of the T-allele is recessive (in which case a single T-allele does not increase the risk), dominant (in which case one or two T-alleles induce the same increase in risk), or additive (in which case the increase in risk is proportional to the number of T-alleles). However, data on plasma angiotensinogen levels indicate that T-alleles cause a rise in plasma angiotensinogen directly proportional to their number, suggesting an additive model of inheritance.3 23 24 Assuming that each T-allele contributes some effect to the phenotype of hypertension and in the absence of information on the genotype, the use of allele frequency as a surrogate parameter seems justified.
Another potential limitation of the present meta-analysis is the large variation of allele frequency among the control groups, ranging from 0.3117 to 0.495 19 for the 235T-allele, despite the Caucasian origin of all patients. Whether these differences represent true population allele frequencies based on local ethnic variations or whether they are due to chance, bias, misclassification, or methodological error cannot be assessed given the scarcity of information on controls. However, a sensitivity analysis excluding all studies with an 235T-allele frequency among controls smaller than 0.3517 or larger than 0.455 19 revealed identical results (OR: 1.22; 95% CI: 1.10 to 1.29).
A major threat to the validity of meta-analyses is the existence of publication bias when studies with positive results get published but studies with negative results disappear in the investigator's drawer.29 However, the majority of studies included in this meta-analysis failed to detect a positive association, and publication bias therefore does not seem to be a major problem in this topic. Furthermore, calculating the "fail-safe-n"30 suggests that an additional 38 studies with a negative result would be required to overturn the conclusion.
Negative studies always raise the question of sample size and power. Although sample sizes were similar in studies with a positive (n: 194/123 [mean/SD]) and negative association (n: 192/169), the mean difference in AGT 235T-allele frequency between cases and controls in positive studies (0.09) and negative studies (0.02) was statistically significant (P<.01), suggesting that negative studies were sufficiently powered to detect differences in allele frequency similar to those seen in the positive studies but that the observed differences were indeed much smaller.
Given the difficulties and pitfalls of association studies, the reader may well question their utility for approaching the genetics of hypertension. It is, however, important to recognize that while linkage studies provide a reasonable strategy for the identification of candidate gene loci, the usefulness of an allelic variant as a diagnostic or prognostic marker or in the identification of a group requiring a specific therapeutic strategy can only be determined with the help of association studies. Thus, while a positive association does not necessarily prove a causal relationship, it can provide useful information regarding the clinical importance of a genetic marker. It should be clear, therefore, that linkage and association studies are complementary, each providing a different type of information.31
To counteract the methodological problems associated with case-control studies, new approaches have been suggested32 33 34 that are less susceptible to effects of population stratification or improper controls. In these so-called "family-based association studies," cases remain the same but homogeneity of the control group is increased by recruiting individuals from within the same families. Thus, for example, one strategy involves the recruitment of affected individuals and their parents, whereby the genotype or allelic frequency of the "control" population is calculated from the frequency of the parental "control" alleles that were not inherited by the case subjects.34 35 This technique, also called the "affected family-based control approach," thus provides an "internal control" for allele or genotype frequencies that is well matched for ethnic ancestry. Although these techniques will demand more efforts to recruit suitable families, the additional information would be extremely useful in distinguishing a spurious from a genuine association,34 and its superiority to linkage studies regarding statistical power has been demonstrated recently by Risch and Merikangas,36 especially in situations in which only a moderate to weak risk is suspected.
Recently further evidence has been presented on how the angiotensinogen gene may play a functional role in the development of hypertension. Thus, the AGT 235T-variant has now been found to be in almost complete linkage disequilibrium with a guanine-to-adenosine transition at -6 bp upstream of the initiation site of transcription.4 In vitro tests of promoter activity and DNA-binding studies with nuclear proteins show that this nucleotide substitution affects the basal transcription rate of this gene in various cell lines, thereby possibly providing an explanation for the association between the AGT 235T-variant and increased plasma levels of angiotensinogen.3 Interestingly, both the adenosine at -6 and threonine at codon 235 of the angiotensinogen gene are now considered to represent the ancestral form of the angiotensinogen gene, because both variants are also present in a variety of primates including chimpanzees, gorillas, and macaques.4 Accordingly, it appears that the neomorphs (guanine at -6 and methionine at codon 235) are associated with a decreased risk of hypertension, whereas it is the ancestral version of the gene that apparently confers an increased risk for developing hypertension. Importantly, as a result of the virtually complete linkage disequilibrium between the -6A and 235T variants, the findings with regard to 235T found in our present meta-analysis can be directly extended to the functional -6A variant of this gene.
In conclusion, despite methodological shortcomings of most studies, the current meta-analysis revealed a statistically significant, albeit weak, increase in risk for hypertension associated with the AGT 235T-allele. It can therefore not be ruled out that an association between the AGT 235T-variant and hypertension does indeed exist. However, further studies with a more rigorous design are clearly warranted to conclusively establish an association between the AGT 235T-allele and essential hypertension in whites.
Received April 14, 1997; first decision May 8, 1997; accepted July 9, 1997.
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