Published online before print January 28, 2008, doi: 10.1161/HYPERTENSIONAHA.107.100370
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(Hypertension. 2008;51:778.)
© 2008 American Heart Association, Inc.
Original Articles |
Meta-Analysis of the Association of 4 Angiotensinogen Polymorphisms With Essential Hypertension
A Role Beyond M235T?
From the Heart Institute (InCor) (T.V.P., A.C.P., J.E.K.) and Clinical and Toxicological Analysis Department (M.R.), Faculty of Pharmaceutical Sciences, University of Sao Paulo Medical School, São Paulo, Brazil; Division of Nephrology (A.C.F.N.), São Paulo University Medical School, University of São Paulo, São Paulo, Brazil; and the Department of Human Functional Genomics (Y.Y.), Life Science Research Center, Mie University, Mie, Japan.
Correspondence to José E. Krieger, InCor, Laboratório de Genética e Cardiologia Molecular/LIM 13, Av Dr Enéas Carvalho Aguiar, 44, São Paulo–SP, CEP-05403-000, Brazil. E-mail krieger{at}incor.usp.br
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Abstract |
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Angiotensinogen (AGT) gene polymorphisms have been linked to increased risk of hypertension, but the data remain controversial. In this study we review the most commonly investigated polymorphisms at the AGT locus (other than M235T) and provide summary estimates regarding their association with essential hypertension, while addressing heterogeneity, as well as publication biases. Data on 26 818 subjects from 46 studies for the 4 most-studied AGT variants (T174M in exon 2 and 3 promoter variants: A-6G, A-20C, and G-217A) were meta-analyzed. Statistically significant associations with hypertension were identified for the T174M (odds ratio [OR]: 1.19; 95% CI: 1.07 to 1.33; P=0.002) and G-217A (OR: 1.37; 95% CI: 1.17 to 1.59; P=0.00006) polymorphisms. A dual but consistent effect was observed for the –20C allele, which was associated with a decreased risk of hypertension in populations of mixed and European ancestries (OR: 0.64; 95% CI: 0.44 to 0.92; P=0.02 and OR: 0.77; 95% CI: 0.65 to 0.91; P=0.003, respectively), but with a 24% increase in the odds of hypertension in Asian subjects (OR: 1.24; 95% CI: 1.04 to 1.48; P=0.02). No association of the A-6G variant with hypertension was detected. Current studies support the notion that single variants at the AGT might modulate the risk of hypertension but indicate caution in interpreting these results because of the putative presence of publication bias and gene-environment interactions.
Key Words: angiotensinogen • hypertension • polymorphism • meta-analysis • T174M • M235T
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Introduction |
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Increased interest in the angiotensinogen (AGT) genetic variation and hypertension has triggered >500 genetic association studies during recent years.1 The linkage of AGT with essential hypertension has been observed even in populations with distinct ancestries.2 Furthermore, we also demonstrated a dose-dependent association between the 235T allele and blood pressure, considered as a continuous trait, in a large, ethnically mixed urban population sample3 and a positive association of this gene variant with coronary artery disease severity.4 Moreover, positive additional evidence from gene titration in mice makes the AGT one of the most promising candidate loci for essential hypertension.1 However, the role of the M235T polymorphism in hypertension remains controversial,5 whereas the 235T allele fails to fully explain the molecular mechanism involved in increased AGT plasma levels. In this context, detailed DNA sequence analyses revealed additional polymorphisms in the promoter region of AGT that may influence blood pressure phenotypes (Figure S1, available in the online supplementary data, at http://hyper.ahajournals.org).1,2
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Therefore, here we report the results of 4 comprehensive meta-analyses on the effects of 4 important polymorphisms at the AGT (namely, T174M polymorphism in the exon 2 and the A-6G, A-20C, and G-217A variants in the promoter region) on the risk of essential hypertension. We provide summary estimates while addressing heterogeneity and publication bias among study results, as well as differences in linkage disequilibrium (LD) structure at AGT among populations of distinct ancestries.
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Materials and Methods |
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Genetic Variants and Inclusion/Exclusion Criteria
In addition to the M235T variant,
7 other polymorphisms at the AGT have been studied, but only those variants studied in >4 independent populations were analyzed. Table S1 depicts the studied polymorphisms, providing information on functional characteristics of examined variants. For further information on inclusion/exclusion criteria, search strategy, and search terms see the online supplemental data.
End Point and Genetic Model
The main end point was the effect of the 4 variants of AGT on blood pressure as a categorical variable (risk of hypertension), which was evaluated using the odds ratio (OR) and its 95% CI. A rationale by which variants at AGT are linked to an increased risk of hypertension is presented in the online supplemental data.
We assumed both dominant and codominant models of inheritance, because previous studies showed an additive effect of T174M and M235T polymorphisms on angiotensinogen and blood pressure levels,2 and primary studies have based their results mainly on both dominant and codominant models of inheritance.3
Statistical Analysis
We assessed heterogeneity among study results using the Q-statistic,6 the I2, which is the proportion of total variance of the pooled effect measure because of between-study variance, and the H metric.7 I2 ranges from 0% to values >99%, whereas the H statistic takes values 1.0, with values >1.3 denoting heterogeneity. For the I2 metric, we assumed that values >30% were suggestive of the presence of heterogeneity.8,9
For the dominant model, we calculated the OR for carriers of the high-risk allele compared with those homozygous for the nonrisk allele (T174M: MM+MT versus TT; A-6G: AA+AG versus GG; A-20C: CC+CA versus AA; and G-217A: AA+AG versus GG, respectively). In a codominant model, the risk associated with heterozygote individuals falls between the risks of both homozygote subjects. Under such a model of inheritance, we obtained the logarithm of OR and its SE for each study from a logistic regression model coding wild-type homozygotes as 0, heterozygotes as 1, and subjects homozygous for the high-risk allele as 2. The codominant OR describes the proportionate rate at which the predicted OR changes with the addition of 1 copy of the high-risk allele.
The summary ORs were estimated using both fixed- (inverse variance method) and random-effects (DerSimonian-Laird method) models.6 The fixed-effects model assumes homogeneity among study estimates and was used for meta-analyses in which statistical tests did not indicate evidence for heterogeneity. Conversely, when heterogeneity is present, a random-effects model is usually more appropriate, because it takes into account the between-study variability. To examine putative sources of heterogeneity, a random-effects metaregression of the logarithm OR was also fitted, where the between-study variance was estimated with the restricted maximum likelihood approach. Year of publication, impact factor (Journal of Citation Reports 2005), triglycerides, total cholesterol, body mass index, and proportion of males were assigned as predictors. When not available, journal impact factor was set as 0.
Evidence for publication bias was assessed using Egger’s test and the Begg-Mazumdar statistic, as well as with visual funnel plot inspection.10 We analyzed the LD relationships of markers covering the entire AGT gene in 3 major human geographic groups (European-derived individuals, Asians, and Africans), as described elsewhere.8,9 For detailed information on such analyses see the online data supplement. P<0.05 was judged significant with the exception of the Q-statistic and publication bias tests, where a significance level of <0.1 was chosen. Statistical analyses were performed with the Stata 9.0 software.
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Results |
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Search Results and Study Characteristics
Forty three of 380 potentially relevant articles met our inclusion criteria. Contact with experts enabled the retrieval of 2 unpublished studies (5126 subjects). In addition, data from the Framingham Heart Study (1487 subjects) were downloaded from CardioGenomics database (http://cardiogenomics.med.harvard.edu), yielding 46 available studies encompassing a total of 26 818 individuals. The characteristics of the 46 included studies and a flowchart schematizing the selection process are presented in Tables S2 through S5 and Figure S2, respectively.
Current Studies Support a Role for the T174M Polymorphism, but Publication Bias May Be Present
Thirty-four studies from 25 publications,11–35 1 unpublished study (Dr Antje Nordwig, Martin-Luther-Universität, available at http://dispatch.opac.d-nb.de), and the Framingham Study provided data on the association of the T174M variant with hypertension (11 079 subjects: 5271 hypertensive and 5808 normotensive subjects). The overall (random-effects model) per-allele risk (codominant model), including all of the studies was 1.19 (95% CI: 1.07 to 1.33; P=0.002). Analysis by ancestry revealed that, whereas in Asian and mixed populations the 174M allele may be associated with an augmented hypertension risk (OR: 1.31; 95% CI: 1.02 to 1.69; P=0.04 and OR: 1.43; 95% CI: 1.11 to 1.83; P=0.005, respectively), no clear evidence for a role of this variant is observed in European descendant populations (OR: 1.03; 95% CI: 0.92 to 1.15; P=0.61). However, the funnel plot suggests asymmetry (Figure S3A), whereas the Egger’s test is significant (P=0.07), denoting the possibility of publication bias and/or genetic heterogeneity. A random-effects metaregression, as well as a linear correlation analysis between logarithm OR for the T174M polymorphism and corresponding logarithm OR for the M235T (when available), failed to indicate any relationship between study characteristics and study results. For more information on such analyses and the forest plot regarding the effect of the T174M polymorphism on the hypertension risk, see Figures S4 and S5, respectively.
Heterogeneous Association of the A-6G Polymorphism With Hypertension
There was significant heterogeneity in relation to both size and direction of effect of the A-6G variant among the 21 published available articles,11,12,21,23,27,36–51 a large unpublished study performed in Japanese (Dr Yoshiji Yamada, available on request) and the Framingham Study (31 substudies with a total of 7664 hypertensive and 7273 normotensive subjects) on the relation between the A-6G polymorphism and hypertension (Q-Statistic, P<0.001; I2=63.8%; H=1.7). ORs were not significant, either considering all of the studies or after stratification by ancestry. Figure S6 shows individual study results and the main analysis of the influence of the –6G allele on the risk of hypertension. No evidence for publication bias was observed, as assessed by statistical tests (Egger’s test, P=0.31 and Begg’s test, P=0.58) or funnel plot inspection (Figure S3B). For complete information on the analysis of the relationship between A-6G polymorphism and hypertension risk, see the online supplemental data.
Contrasting Effects of the A-20C Polymorphism on Risk of Hypertension Among Individuals of Distinct Ancestries
A total of 13 studies from 9 publications20,23,24,36,37,42,50,52,53 and the Framingham Study, encompassing 4984 subjects, were combined in the meta-analysis investigating the association of the A-20C variant with hypertension. Surprisingly, a contrasting but consistent effect of the –20C variant on hypertension risk was observed when studies were considered separately by ancestry (Figure 1). Indeed, the –20C allele was associated with a significant decrease in hypertension risk in populations of European (OR: 0.77; 95% CI: 0.65 to 0.91; P=0.003) and mixed ancestries (OR: 0.64; 95% CI: 0.44 to 0.92; P=0.02) but was found to be associated with a 24% increase in the odds of hypertension in individuals of Asian descent compared with the A-20 allele (OR: 1.24; 95% CI: 1.04 to 1.48; P=0.02). Evidence of publication bias was not observed by either statistical assessment (Egger’s test, P=0.95 and Begg’s statistic, P=0.46), as well as funnel plot asymmetry (Figure S3C). Similar results were obtained under a dominant model of inheritance (random-effects model: CC+CA versus AA): ORs for European-derived, Asian and mixed populations were 0.75 (95% CI: 0.61 to 0.90; P=0.003), 1.33 (95% CI: 1.09 to 1.64; P=0.006), and 0.54 (95% CI: 0.34 to 0.85; P=0.007), respectively.
Positive Association Between the –217A Allele and Hypertension
Six studies from 5 publications20,27,44,45,54 resulted in 1429 hypertensive and 1085 normotensive subjects, which did not allow for ancestry analysis. No evidence for heterogeneity was observed (Figure 2), suggesting a similar effect of the G-217A polymorphism on the risk of hypertension across studies. Under a codominant model of inheritance (per-allele risk), 1 additional copy of the –217A variant was associated with a 37% increase in the odds of hypertension (OR: 1.37; 95% CI:1.17 to 1.59; P=0.00006). The corresponding result under a dominant model of inheritance (AA+AG versus GG) was quite similar and also consistent with a significant effect of the –217A allele on hypertension risk (OR [fixed-effects model]: 1.37; 95% CI: 1.15 to 1.63; P=0.0005). Neither statistical tests (see online supplemental data) nor visual inspection (Figure S3D) demonstrated evidence for publication bias. Figure 2 depicts the individual study results, as well as pooled estimates under a codominant model of inheritance.
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LD Pattern at the AGT Locus
A distinct pattern of LD among populations of different ancestries was observed (Figure S7). Interestingly, the rs5050 marker (A-20C) presents a more-pronounced degree of LD in Asian subjects compared with either Africans or European-derived subjects. In fact, this variant presents an absolute D' value of >0.9 (log of odds score: 2) with 25 of 43 analyzed polymorphisms for individuals of Asian descent, whereas this estimate decreases to 20 and 13 for European-derived and African subjects. For further information on structure of blocks, as well as specific LD patterns, see the online supplemental data.
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Discussion |
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Main Findings
This study analyzed data on 26 818 subjects, providing 4 main conclusions. First, the T174M polymorphism may be associated with increased hypertension risk, although publication bias cannot be ruled out. Second, an erratic effect of the A-6G variant on hypertension risk is observed, with no substantial evidence for a relationship between the A-6 allele and augmented susceptibility to high blood pressure, considering all of the studies together. Third, a dual, but consistent, effect of the A-20C variant on the risk of hypertension within each ancestry group is evident, making this variant a target for additional investigations. Finally, an interesting and quite consistent effect of the G-217A promoter variant on the risk of hypertension may exist, suggesting the –217A allele to be a polymorphism associated with a higher susceptibility to hypertension.
Study Limitations
Publication bias tests and the visual inspection of the funnel plot asymmetry are powerful tools only when the number of studies is large.10 Thus, the small number of articles investigating the relationship between the A-20C and G-217A variants and hypertension prevents a convincing statement about the absence of small study bias in this set of studies. Secondly, the strong heterogeneity observed in the relationship between the A-6G polymorphism and hypertension precludes a consistent estimate of the effect of this variant, even when analyzed by ancestry. In this respect, we failed to obtain all of the study-level covariates, because a number of studies did not report relevant data, and several original authors did not provide all of the relevant information, precluding a more robust assessment of sources of heterogeneity.
The Influence of the T174M Polymorphism on the Susceptibility to Hypertension Is Still Unclear
The effect of the T174M on the risk of hypertension was observed in Asians and diverse-ancestry populations but not in European-derived populations. Although no functional evidence is available, we speculate based on modeling analysis that the T174M polymorphism may lead to abnormal function of the human AGT protein (Figure S8). The effect of the T174M variant on plasma AGT levels is largely unavailable; thus, the influence of the T174M polymorphism on susceptibility to hypertension remains unclear. We found no correlation between the effects of the T174M and the M235T polymorphisms, suggesting either a specific effect of the 174M variant among different ethnic groups or biases toward the dissemination of "positive" results by non-European–derived studies.9
A-6G and Hypertension: A Role for the M235T Polymorphism or Gene-Environment Interactions?
The effect of the M235T polymorphism on blood pressure has been hypothesized to be because of strong LD between this variant and the promoter A-6G polymorphism, which was reported to increase AGT transcriptional activity compared with the G allele.2 Thus, the null results regarding the relationship between the A-6 allele and hypertension in all of the ancestry groups, obtained herein, do not support the accepted view that the 235T acts uniquely as a surrogate marker, indicating additional complexity for the understanding of the molecular basis of interactions among AGT polymorphisms in vivo.
However, importantly, our results do not rule out a potential association of the A-6G variant with hypertension. Indeed, the I2 value for the overall relation between the A-6G polymorphism and hypertension risk is intriguing, and, to our knowledge, is one of the highest values of heterogeneity found for a meta-analysis of genetic association studies. One explanation for the observed heterogeneity might be gene-environment interactions. In fact, Hunt et al41 suggested, on prospective examination of 1509 European-derived subjects, that the A-6 variant might be a risk factor only in subjects with a standard diet, whereas the A-6 variant might be a protective factor in individuals submitted to a low-sodium diet indicating the importance of gene-environment interactions, suggesting that evolutionary aspects should not be neglected in genetic association studies.1
Evidence From In Vitro Studies Reinforces the Role of the A-20C and G-217A Variants in the Risk of Hypertension
Previous studies have demonstrated that plasma angiotensinogen levels increase linearly with the number of –20C alleles, with subjects with the CC genotype associated with the highest plasma levels of AGT.53 Similar results were also reported for the G-217A variant, in which the –217A allele was found to be associated with increased basal transcription activities when compared with the G-217 variant.54 Furthermore, Dickson et al55 provided further support for a role of these 2 variants, demonstrating that the A-20C and G-217A polymorphisms have the largest influence on angiotensinogen transcription in vitro, suggesting that these polymorphisms might be major predisposing factors for hypertension.
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Conclusions |
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Our findings suggest that the A-20C and G-217A polymorphisms, in the promoter region of the AGT, may influence the risk of hypertension, whereas current data on the T174M variant and blood pressure are less consistent and may be influenced by publication bias. Finally, the A-6G polymorphism effect on hypertension might be more pronounced in populations with a salt-rich diet, further emphasizing the need to address genetic influences in a context-dependent manner.
Perspectives and Directions for Future Research
Few studies explored the association of the A-20C and G-217A variants with blood pressure as a continuous variable, indicating that the effect of the –20C and –217A alleles on blood pressure levels requires further investigation. Likewise, because most studies have focused on hypertension in subjects aged 50 years, larger, well-designed association studies in a younger population of hypertensive subjects are of interest, because genetic factors may play a major role in young-onset hypertension, especially for those subjects with familiar histories of hypertension,56 whereas environmental factors are likely to contribute more prominently than the genetic component to blood pressure in older subjects.
Importantly, substantial evidence indicates a more important role for epistatic and gene-environment interactions, as well as haplotypic effects in hypertension susceptibility.9,29,45 Thus, failure to account for haplotypic structure and/or ethnicity-specific interactions between genetic polymorphisms and environmental factors might explain the dual effect of the A-20C polymorphism on the risk of hypertension in populations of different ancestries, suggesting that additional studies assessing haplotypic analysis, as well as gene-environment interactions, will be necessary. Lastly, although further analyses are warranted to elucidate the role of the 174M allele in hypertension susceptibility, future studies on the A-6G and hypertension should concentrate on gene-environment interactions, particularly on the influence of the A-6 variant on blood pressure in populations with different salt intake habits.
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Acknowledgments |
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We thank all of the investigators, whose original work enabled us to perform the present meta-analyses, and the HapMap Project for making the information available.
Sources of Funding
T.V.P. was supported by a fellowship from Coordenação de Aperfeiçoamento Pessoal de Nível Superior, Department of Biochemistry and Molecular Biology, Federal University of São Paulo, Brazil. This work was funded by grants from Fundação de Amparo à Pesquisa de São Paulo to J.E.K. and Fundação Zerbini.
Disclosures
None.
Received August 23, 2007; first decision September 17, 2007; accepted January 4, 2008.
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