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Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1269-1275
Published online before print June 12, 2003, doi: 10.1161/01.ATV.0000079007.40884.5C
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1269.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Angiotensinogen Gene Polymorphism, Plasma Angiotensinogen, and Risk of Hypertension and Ischemic Heart Disease

A Meta-Analysis

Amar Akhtar Sethi; Børge Grønne Nordestgaard; Anne Tybjærg-Hansen

From the Department Clinical Biochemistry (A.A.S., B.G.N.), Herlev University Hospital and Department Clinical Biochemistry (A.T.H.), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Correspondence to Anne Tybjærg-Hansen, MD, DMSc, Department of Clinical Biochemistry, KB3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. E-mail at-h{at}rh.dk


*    Abstract
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Objective— The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations.

Methods and Results— One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%; P=0.0004) in MT heterozygotes and 11% (7% to 15%; P<0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.

Conclusions— Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.


Key Words: meta-analysis • blood pressure • genetics • hypertension • cardiovascular disease


*    Introduction
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Hypertension is a multifactorial disorder because of the interaction of many risk genes and environmental factors such as obesity, dietary salt intake, alcohol consumption, and stress. Approximately 20% to 60% of the population variability in blood pressure is genetically determined.1 In the first report linking a gene to hypertension, Jeunemaitre et al2 suggested that the M235T polymorphism in the angiotensinogen gene in the homozygous TT state was associated with an approximate 20% increase in plasma angiotensinogen and an odds ratio for hypertension of 1.95 compared with the MM wild type. The mechanistic explanation behind this was that a higher throughput in the renin-angiotensin system might increase blood pressure by the actions of angiotensin II on sodium reabsorption in the kidneys and by vessel constriction. Apart from hypertension, which is a well-established risk factor for ischemic cardiovascular disease, many researchers were also prompted to investigate whether polymorphisms in the angiotensinogen gene were independent risk factors for ischemic cardiovascular disease.3,4

In the last decade, hundreds of studies either supporting or rejecting the findings of the initial study2 have been published. In the late 1990s, 3 independent meta-analyses5–7 suggested a 22% to 32% increase in risk of hypertension in Japanese and white individuals carrying the TT genotype. The largest of these meta-analyses included 20 397 individuals.6 With the publication of several more recent studies, including our own studies based on the Copenhagen City Heart Study,4,8 the present meta-analysis now includes 45 267 individuals and investigates the association of M235T with plasma angiotensinogen levels and systolic and diastolic blood pressure with the risk of hypertension, ischemic heart disease, and myocardial infarction in 3 different ethnic groups stratified by sex.


*    Methods
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Data Sources
A computerized literature search on PubMed from January 1992 until March 2002 was performed using the following index terms: angiotensinogen gene, mutations, polymorphisms, systolic blood pressure, diastolic blood pressure, pulse pressure, angiotensinogen concentration, angiotensinogen levels, plasma angiotensinogen, hypertension, essential hypertension, elevated blood pressure, ischemic heart disease, coronary artery disease, myocardial infarction, ischemic cerebrovascular disease, and stroke. The following constraints were applied to the search: (1) only articles in English were used; (2) studies were only on human subjects; and (3) at least one of the polymorphisms was examined in the angiotensinogen gene: M235T, T174M, G(-6)A, or A(-20)C. Furthermore, reference lists of published studies were assessed and reviews scrutinized for missing studies. This search identified 471 articles.

Study Selection
Only studies examining the association of angiotensinogen gene polymorphisms with either plasma angiotensinogen levels, systolic or diastolic blood pressure, risk of hypertension, or risk of ischemic heart or ischemic cerebrovascular disease were selected. This selection left 127 studies that were scrutinized in detail, but because there were very few studies (between 1 and 4 studies) of each the A(-20)C, G(-6)A, and T174M polymorphisms, the present meta-analyses were restricted to M235T. Because only 2 studies examined M235T and risk of ischemic cerebrovascular disease,4,9 this end point was excluded.

The exclusion criteria (see http://atvb.ahajournals.org) restricted the number of studies to 9 on plasma angiotensinogen levels (Table I, available online at http://atvb.ahajournals.org), 11 on systolic and diastolic blood pressure (Table II, available online), 41 on hypertension (Table III, available online), and 21 on ischemic heart disease and myocardial infarction (Table IV, available online). In total, these meta-analyses included 63 studies with 45 267 participants; 36 studies were excluded (table available from authors).


*    Results
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Tables I through IV (available online) show the characteristics of studies included in this meta-analysis of associations of M235T in the angiotensinogen gene with plasma angiotensinogen levels, systolic and diastolic blood pressure, risk of hypertension, and risk of ischemic heart disease and myocardial infarction, respectively. Average allele frequencies of 235T were 0.43 in white subjects, 0.76 in Asian subjects (versus white subjects, P=0.000), and 0.83 in black subjects (versus white subjects, P=0.000; versus Asian subjects, P=0.1).

Association of M235T Genotype With Plasma Angiotensinogen Levels
Plasma angiotensinogen level was significantly increased in white MT heterozygotes by 5% (95% CI, 2 to 8; P=0.0004) and in TT homozygotes by 11% (7% to 15%; P<0.00001) compared with MM homozygotes (Figure 1). When stratified by sex or ± hypertension, the increase in plasma angiotensinogen levels when comparing MT or TT individuals versus MM were (1) 4% (-2% to 10%; P=0.18) and 13% (7% to 19%; P=0.00004), respectively, in women; (2) 6% (1% to 11%; P=0.02) and 11% (5% to 17%; P=0.0006), respectively, in men; (3) 4% (1% to 7%; P=0.01) and 10% (6% to 14%; P<0.00001), respectively, in normotensive subjects, and (4) 7% (2% to12%; P=0.01) and 12% (4% to 20%; P=0.002), respectively, in hypertensive subjects. Test of heterogeneity was significant (P=0.004) for studies on white hypertensive subjects (TT versus MM), reducing the effect size from 12% to 8% (-17% to 33%; P=0.5) when applying the random effects model.



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  		Figure 1. Plasma angiotensinogen levels (% of MM) as a function of M235T genotype. Effect size (mean % and 95% CI) for MT versus MM (left) and TT versus MM (right) in white, Asian, and black subjects. Effect sizes stratified by sex and ± hypertension are shown for white subjects. *Significant heterogeneity test.

Increases in plasma angiotensinogen levels in Asian and black subjects were nonsignificant for all comparisons with the MM genotype, which in these populations accounts for only approximately 4% of individuals as opposed to 25% to 35% in white subjects. The number of studies in each of these ethnic groups was limited to 1 or 2 (Figure 1).

Association of M235T Genotype With Blood Pressure As a Continuous Variable
Association of M235T genotype with variation in systolic and diastolic blood pressure were nonsignificant for all comparisons in both white subjects (total and stratified by sex) and Asian subjects (Figure 2; data not shown for diastolic blood pressure). Associations were also nonsignificant when the random effects model was applied. One Asian study10 suggested an association between 235T and decreased systolic blood pressure, resulting in significant tests of heterogeneity for both comparisons (MT versus MM, P=0.0002; TT versus MM, P=0.0003). Exclusion of this particular study10 removed the heterogeneity, and the associations of genotype with increased systolic blood pressure became significant for both comparisons (MT versus MM,+2.9 mm Hg [0.02 to 5.7]; P=0.05; TT versus MM,+3.2 mm Hg [0.4 to 5.9]; P=0.02). Heterogeneity was also found in analyses of diastolic blood pressure, but associations remained nonsignificant when the study by Suwazono et al10 was removed.



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  		Figure 2. Systolic blood pressure (mm Hg) as a function of M235T genotype. Effect size (mean % and 95% CI) for MT versus MM (left) and TT versus MM (right) in white and Asian subjects. Effect size stratified by sex shown for white subjects. *Significant heterogeneity test.

Association of M235T Genotype With Blood Pressure As a Dichotomous Variable
White MT and TT individuals had a pooled odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) and 1.19 (1.10 to 1.30), respectively, compared with the MM genotype (Figure 3). Test for heterogeneity was significant for the comparison of TT versus MM (P=0.006), and the odds ratio increased to 1.29 (1.10 to 1.50) when applying the random effects model. M235T genotype was associated with similar trends when data were stratified by sex.



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  		Figure 3. Risk of hypertension in white, Asian, and black subjects as a function of M235T genotype. Odds ratio (95% CI) for MT (left) and TT (right) versus MM. Odds ratio stratified by sex shown for white and Asian subjects. *Significant heterogeneity test.

Asian MT and TT individuals had a pooled odds ratio for hypertension of 1.29 (0.96 to 1.74) and 1.60 (1.19 to 2.15), respectively, compared with MM homozygotes (Figure 3). Furthermore, a test for linear trend was significant (OR, 1.23 [1.11 to 1.37]; P=0.0001). Genotype was associated with similar trends when data were stratified by sex.

In black subjects, M235T genotype did not predict risk of hypertension (Figure 3), and in addition, test for linear trend was not significant (OR, 1.15 [0.90 to 1.45]; P=0.26).

Association of M235T Genotype With Risk of Ischemic Heart Disease and Myocardial Infarction
No significant change in the risk of ischemic heart disease or myocardial infarction was found for MT or TT individuals compared with MM homozygotes (Figure 4); this was true for both white and Asian subjects and for both pooled data and data stratified by sex. No significant trend test was found for Asian subjects (OR, 1.13 [1.00 to 1.29]; P=0.06). Seven of 18 analyses were tested significant for heterogeneity, but odds ratios remained insignificant when random effects models were applied.



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  		Figure 4. Risk of ischemic heart disease in white and Asian subjects as a function of M235T genotype. Odds ratio (95% CI) for MT (left) and TT (right) versus MM. Separate analysis for myocardial infarction as well as sex-stratified results are shown. *Significant heterogeneity test.


*    Discussion
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 *Discussion
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In the present meta-analysis of 45 267 subjects, the M235T mutation in the angiotensinogen gene was associated with a 5% increase in levels of plasma angiotensinogen in white MT heterozygotes, which increased to 11% in white TT homozygotes compared with MM homozygotes. In agreement with this, white MT heterozygotes and TT homozygotes had a significant 8% and 19% increase in risk of hypertension, respectively, compared with MM homozygotes. A similar trend was observed in Asian individuals, where TT homozygotes had a 60% increased risk of hypertension compared with MM homozygotes whereas MT heterozygotes had an intermediate though borderline increase in risk. Finally, these trends were similar in both sexes in both ethnic groups.

The present meta-analyses adds an important new insight, because previous meta-analyses were smaller and only examined Japanese subjects,7 only examined white subjects,5 or included some highly selective patients and even used some individuals twice.6

Plasma Angiotensinogen Levels
The present results correspond well with those of a previous meta-analysis,6 although for the subgroup analysis of women we found effect sizes less than half of those previously reported. This discrepancy could be attributable to ethnic heterogeneity in the former meta-analysis or that the number of women investigated was only half that of the present study.

The increase in plasma angiotensinogen levels in white subjects was similar for the various subgroup analyses. We cannot confirm nor reject an association between M235T and angiotensinogen levels in Asian subjects, because there was only 1 study included in this analysis. The results can only be used to compare plasma angiotensinogen levels between ethnic groups and do not exclude an association between M235T and plasma angiotensinogen levels in Asian subjects. Because M235T is associated with a stepwise increase in risk of hypertension as a function of genotype, it seems reasonable that genotype would predict increased levels of angiotensinogen if investigated in a larger sample.

In addition to the smaller number of participants, high allele frequencies of 235T (0.80 to 0.95)11–13 in both Asian and black compared with white subjects ({approx}0.40 to 0.50)8,14,15 could explain the lack of positive findings in these ethnic groups, because a very large number of individuals would be required to detect even a moderate association with genotype.

Blood Pressure As a Continuous Variable
Systolic and diastolic blood pressure did not change as a function of M235T genotype in 10 315 healthy white and Asian subjects. However, when excluding the study by Suwazono et al10 from the analyses in Asian subjects, effects sizes became just significant for systolic blood pressure in both comparisons. The results of Suwazono et al may at least in part be explained by the fact that they selected their population by ± hypertension (68 subjects with blood pressure >=140/90 mm Hg and 128 with blood pressure <140/90 mm Hg). If the T-allele is associated with hypertension as suggested in the present meta-analysis, this allele would be underrepresented in the study of Suwazono et al, and this could influence their findings. Even though a mild increase in systolic blood pressure is observed, it must be interpreted with caution, and more studies would be needed to rule out chance findings.

In contrast to our findings, a previous meta-analysis6 found systolic and diastolic blood pressure slightly elevated (2.15 mm Hg, P=0.02 and 1.48 mm Hg, P=0.04, respectively) when TT homozygotes were compared with MM individuals in 5289 subjects of mixed ethnic origin. However, this meta-analysis included (1) studies not only of healthy individuals but also of patients with diabetic nephropathy and ischemic cerebrovascular disease; (2) intervention studies; and (3) population studies of mixed ethnic origin. The above-mentioned patient categories are normally characterized by high blood pressure values because of their primary disease. If 235T is associated with hypertension, positive findings might be more likely in these groups. Likewise, lack of association of genotype with variation in blood pressure in our study might be attributable to the association being too mild to be detected in a healthy population or to misclassification of some individuals, which is more likely, because blood pressure in many studies relied on a single measurement.

Blood Pressure As a Dichotomous Variable
We found a modest but significant increase of 8% and 19% in white MT and TT individuals. Asian TT homozygotes had a 60% increased risk of hypertension compared with MM homozygotes as well as a significant test for linear trend (OR, 1.23; P=0.0001). Our findings correspond well with earlier meta-analyses5–7 and do not suggest that the relations between this polymorphism and hypertension are different in Asian compared with white individuals, as has been reported previously.6 However, the latter study had less than half the number of subjects of the present meta-analysis (n=1995 versus 5181) and only found a significant association for heterozygous individuals, suggesting perhaps that this was a chance finding.6

Neither previous meta-analyses nor the present meta-analysis found an association between M235T and hypertension in black subjects. A possible explanation could be the very high-allele frequency of 235T in black individuals, making it very difficult to detect mild associations unless examining a very large population sample.

Risk of Ischemic Heart Disease
Lack of an association in the present meta-analysis between M235T and risk of ischemic heart disease or myocardial infarction is in agreement with a previous report on white and Asian subjects.6 However, the excess risk of 11% in TT versus MM homozygotes observed in white subjects as well as the test for trend in Asian subjects were both borderline significant (P=0.07 and P=0.06, respectively).

Limitations
Results from the present as well as other meta-analyses should be interpreted with caution, because the quality and reliability of the results depend on the quality of the studies included. Ideally, cases should be matched with controls or at least controls selected from the same background population to take confounding into account. However, studies included in the present meta-analysis were not homogeneous with respect to selection, definition, or characterization of cases and controls. Analyses of hypertension, for example, included 15 studies of cases sampled from the general population, primary care centers, or self-referral centers, whereas 8 studies had cases sampled from special hypertension clinics; controls were selected from various places, such as primary care clinics, the general population, blood donors, previous studies, healthy family registers, spouses, or self-referrals. In addition, 6 of 22 studies recruited subjects for reasons other than investigating hypertension. Very few studies were based on a homogeneous population providing full phenotypic characteristics or detailed selection criteria for cases and controls. The application of standardized rules requiring uniform predefined selection criteria for all participants in any case-control study before publication and entering into meta-analyses has been suggested earlier.6

Although meta-analysis of randomized clinical trials is a straightforward methodology, applying it to nonrandomized studies such as an association study becomes critical because of the great potential of bias within each of the pooled studies. The meta-analysis by itself cannot make these biases disappear.

A major drawback of this meta-analysis, which examines multifactorial disorders such as hypertension, is the methodological failure to provide results adjusted for some of the most important risk factors, eg, age and smoking, resulting in the confounding of phenotype in cases and controls.16 Although publication bias cannot be excluded, we believe it to be a minor problem in the present meta-analysis, because each funnel plot was independently scrutinized by 2 authors and no evidence of publication bias was found. Finally, a limitation of this study is that our results were extracted directly from published articles and not from original data provided by the authors.


*    Conclusions
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *Conclusions
down arrowReferences
 
In the present meta-analysis of 45 267 subjects, M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a significant but moderate increase in risk of hypertension in both white and Asian subjects. Genotype did not predict (1) plasma angiotensinogen levels in Asian and black subjects, (2) hypertension in black subjects, or (3) systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.


*    Acknowledgments
 
Supported by The Danish Heart Foundation, The Danish Medical Research Council, The University of Copenhagen, The European Organization for the Control of Circulatory Diseases, The Beckett Fund, Manufacturer Frands Køhler Nielsen and Wife’s Grant, and King Christian the Xth Fund.

Received January 13, 2003; accepted April 22, 2003.


*    References
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 *References
 

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