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Circulation. 2007;116:1356-1366
Published online before print September 10, 2007, doi: 10.1161/CIRCULATIONAHA.107.728857
CLINICAL PERSPECTIVE
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(Circulation. 2007;116:1356-1366.)
© 2007 American Heart Association, Inc.

Coronary Heart Disease

Quantitative Assessment of the Effect of Angiotensinogen Gene Polymorphisms on the Risk of Coronary Heart Disease

Ming-Qing Xu, PhD*; Zheng Ye, PhD*; Frank B. Hu, MD, PhD; Lin He, PhD

From the Bio-X Life Science Research Centre, Shanghai Jiao Tong University, Shanghai, China (M.-Q.X., L.H.); Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (M.-Q.X., L.H.); School of Public Health, Harvard University, Boston, Mass (M.-Q.X., F.B.H.); Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (F.B.H.); and Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (Z.Y.).

Correspondence to Professor Lin He, PhD, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Yuan Rd, Shanghai 200031, China (e-mail helin{at}bio-x.cn); or Dr Ming-Qing Xu, School of Public Health, Harvard University, 651 Huntington Ave, Boston, MA 02115 (e-mail mxu@hsph.harvard.edu).

Received April 9, 2007; accepted July 23, 2007.


*    Abstract
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Background— Angiotensinogen, a key protein in the renin-angiotensin system, plays an important role in cardiovascular hemostasis. Many studies have examined the association between polymorphisms in the angiotensinogen gene and risk of coronary heart disease (CHD), but the results have been inconsistent.

Methods and Results— We performed a meta-analysis of 43 associations studies on 2 angiotensinogen polymorphisms (M235T and T174M) and risk of CHD published before March 2007, including a total of 13 478 CHD cases and 17 024 controls. We also explored potential sources of heterogeneity. In a combined analysis, the summary per-allele odds ratio for CHD of the M235T polymorphism was 1.11 (95% confidence interval, 1.03 to 1.19). However, when the analyses were restricted to 4 larger studies (n >500 cases), the summary per-allele odds ratio was 0.99 (95% confidence interval, 0.94 to 1.04). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the 174M variant showed no significant overall association with CHD, yielding a per-allele odds ratio of 1.07 (95% confidence interval, 0.93 to 1.22).

Conclusions— This meta-analysis suggested an overall weak association between the M235T polymorphism and CHD risk. However, the association was not observed in several larger studies, suggesting a publication bias. Additional very large-scale studies are warranted to provide conclusive evidence on the effects of the angiotensinogen gene and other genes within the renin-angiotensin system on risk of CHD.


Key Words: angiotensinogen • coronary disease • genetics • haplotypes • linkage disequilibrium • myocardial infarction • risk factor


*    Introduction
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Coronary heart disease (CHD) is a leading cause of morbidity and mortality worldwide, affecting millions of people in both developed and developing countries. Despite much investigation, the causes are not yet fully understood. Accumulated evidence suggests that CHD is determined by a complex interaction of both genetic and environmental factors. Evidence is increasing that predisposition to CHD is associated with vascular tone and blood pressure.1–4 Thus, the enzymes involved in their physiological metabolisms have received a great deal of attention.

Clinical Perspective p 1366

The renin-angiotensin system (RAS), a 2-enzyme cascade, plays a central role in the regulation of blood pressure, vascular remodeling, and sodium homeostasis.1,2 Angiotensinogen (AGT), a substrate of the RAS system, is believed to be implicated in the pathogenesis of hypertension and CHD.3,4 Over the last decade, considerable efforts have been devoted to exploring the relationships between the AGT polymorphisms and CHD. However, existing studies have yielded inconsistent results.5–51 These disparate findings may be due partly to insufficient power, false-positive results, and publication biases. The interpretation of these studies has been further complicated by the use of different coronary disease end points (eg, myocardial infarction and coronary stenosis), different populations (white versus other ethnic groups), or different control groups (eg, population versus hospital based).

Several polymorphisms in the exons and promoter region of the AGT gene have been studied in relation to CHD. Only a few studies explored the associations between CHD and polymorphisms in the promoter region of the AGT gene such as A(–6)G, A(–20)C, and G(–217)A. Most studies have focused on 2 single amino acid substitutions in exon 2 [which may affect the basal rate of transcription because of complete linkage disequilibrium with the G(–6)A polymorphism at the promoter site52]: a methionine-to-threonine exchange in codon 235 (or alternatively as the Met and Thr alleles; dbSNP ID, rs699; also referred to as T268M47) and a threonine-to-methionine exchange in codon 174 (dbSNP ID, rs4762), designated the T and M alleles, respectively. A moderate to strong linkage disequilibrium exists between them in various populations (D’=0.48 to 0.91).3,29,47

To help clarify the inconsistent findings, we conducted a meta-analysis of published genetic association studies of these 2 polymorphisms and risk of CHD. This meta-analysis includes 43 studies with a total of 13 478 CHD cases and 17 024 controls. It has twice as many cases as the previous meta-analysis.53 We also conducted a meta-analysis of a closely linked T174M polymorphism (involving a total of 8605 CHD cases and 11 967 controls).


*    Methods
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Data Source
Genetic association studies published before March 2007 on CHD and at least 1 of the 2 polymorphisms in the AGT gene described above were sought by computer-based searches. The definition of CHD is based on the World Health Organization criteria (CHD, also called coronary artery disease, ischemic heart disease, and atherosclerotic heart disease, is the end result of the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium). The search was supplemented by reviews of reference lists for all relevant studies and review articles and correspondence with authors. Computer searches of PubMed, EMBASE, and CNKI (Chinese National Knowledge Infrastructure) used keywords relating to the relevant genes (eg, "angiotensinogen" or "AGT") in combination with words related to CHD (eg, "coronary heart disease," "coronary artery disease," "myocardial infarction," "ischemic heart disease," or "atherosclerotic heart disease") and polymorphism. All relevant reports identified were included without language restriction. Two reports were excluded because of duplication of data.30,32

Data Extraction
The following information was extracted from each report according to a fixed protocol: the first author, publication year and month, study design, ethnicity, definition and numbers of cases and controls, mean age of CHD cases, control status, frequency of genotypes, and Hardy-Weinberg equilibrium in controls. Relevant clinical outcome included confirmed myocardial infarction (generally by World Health Organization criteria) and coronary stenosis (defined variously as at least 50%10,11,13,17,18,20,27,31,34,36,37,39,41,45,48,50 or 70%9,12,23 stenosis of ≥1 major coronary arteries on the basis of computer-assisted assessments). For the M235T polymorphism, sufficient data existed to analyze these outcomes separately.

Statistical Analyses
Deviation from Hardy-Weinberg equilibrium was examined by {chi}2 tests. The per-allele odds ratio (OR) of the rare allele (235T, 174M) was compared between cases and controls by assigning scores of 0, 1, and 2 to common homozygotes, heterozygotes, and rare homozygotes, respectively, and calculating ORs per unit score by logistic regression. Random-effects and fixed-effect summary measures were calculated as inverse-variance–weighted average of the log odds ratio. The results of random-effects summary were reported in the text because it takes into account the variation between studies. Heterogeneity was assessed with the Q-statistic test54 and I2 test, which describes the proportion of variation in the log ORs that is attributable to genuine differences across studies rather than to random error.55 Subsidiary analyses included subgroup analyses or random-effects meta-regression with restricted maximum likelihood.56 Publication bias was assessed with the Egger test,57 Begg test,58 and the trim and fill method,59 which estimates the number and outcomes of potentially missing studies resulting from publication bias. Study design (prospective versus retrospective studies), study size (≥500, 200 to 499, and 200 cases), source of controls (population versus hospital based), ethnicity (white, East Asian, and others), mean age of cases (>55 years, ≤55 years, or unknown), types of CHD end points (myocardial infarction versus coronary stenosis), gender (male or mixed), status of Hardy-Weinberg equilibrium (yes or no), and genotyping procedures (restriction fragment length polymorphism versus other) were prespecified as characteristics for assessment of heterogeneity; other potentially relevant subgroups (such as age and sex) could not be investigated reliably because individual participant data were not available for this meta-analysis. Ethnic group was defined as white (ie, people of white European origin), East Asian, or others (eg, African Indian, African American). All probability values are 2-sided, and values of P<0.05 were considered statistically significant. All statistical analyses were carried out with the Stata software version 8.0 (Stata Corporation, College Station, Tex). In the figures, areas of squares of individual studies are inversely proportional to the variances of the log ORs, and the horizontal lines represent confidence intervals (CIs).

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


*    Results
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Characteristics of the Included Studies
A total of 43 eligible association studies were identified, with 14 studies genotyping >1 variant (Table 1DownDown). For the M235T polymorphism, 41 studies were available, including a total of 13 279 cases and 16 701 controls (weighted mean age of cases, 59.73 years). For the T174M polymorphism, 16 studies involved a total of 8605 cases and 11 967 controls (weighted mean age of cases, 60.56 years). These 2 polymorphisms were found to occur in frequencies consistent with Hardy-Weinberg equilibrium in the control populations of the vast majority of the published studies. Of the cases, 80% were white, 16% were Asian, and 4% were of other ethnic origins (including African American). Of the 43 studies, 40 involved retrospective comparisons, and 3 were prospective in design.24,28,48 Of the 40 retrospective studies, 26 used population-based controls, and 14 used hospital-based controls. All but 5 studies10–12,34,44 used polymerase chain reaction/restriction fragment length polymorphism with various restriction enzymes for genotyping. Of the remaining studies, 2 used oligonucleotide probes,9,10 2 used single-tube bidirectional allele-specific amplification,33,43 and 1 used single-strand conformation polymorphism.11


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  		TABLE 1. Characteristics of Genetic Association Studies of 2 AGT Polymorphisms in the Present Meta-analyses.


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  		TABLE 1. Continued


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  		TABLE 1. Continued

Association of the M235T Variant With CHD
Substantial heterogeneity was present among the 41 studies of the M235T polymorphism (I2=65%; 95% CI, 45 to 72; P<0.0001). Sample size ({chi}22=7.65, P=0.02) explained a large part of the heterogeneity, whereas ethnic group ({chi}22=1.87, P=0.39), source of controls ({chi}21=0.05, P=0.83), genotyping procedures ({chi}21=0.03, P=0.86), status of Hardy-Weinberg equilibrium ({chi}21=0.37, P=0.54), mean age of cases ({chi}22=0.75, P=0.69), and gender ({chi}21=0.02, P=0.89) explained little heterogeneity. Overall, the per-allele OR of the 235T variant for total CHD was 1.11 (95% CI, 1.03 to 1.19; Figure 1), with corresponding results under dominant and recessive genetic models of 1.09 (95% CI, 0.97 to 1.21) and 1.16 (95% CI, 1.05 to 1.28), respectively. Subsidiary analyses of specific CHD end points yielded a per-allele OR for myocardial infarction of 1.05 (95% CI, 0.91 to 1.22; Figure 2) and for coronary stenosis of 1.13 (95% CI, 1.04 to 1.22; Figure 2), with no clear difference between these sub–end points ({chi}21=0.73, P=0.39). A funnel plot of these 41 studies suggested a possibility of the preferential publication of positive findings in smaller studies (Begg test, P=0.04, Figure 3; Egger test, P=0.02, Figure 4). Analysis restricted to the 4 studies6,20,29,47 with at least 500 cases (total, 6760 cases and 9959 controls), which should be less prone to selective publication than smaller studies, yielded an OR of 0.99 (95% CI, 0.94 to 1.04). No heterogeneity was present among the 4 studies of the M235T polymorphism (I2=0%; 95% CI, 0% to 85%; P=0.84). Further evidence of selective publication was suggested by the results of the trim and fill approach, which indicated that 7 missing studies are required to make the funnel plot symmetrical (Figure 5).


Figure 1186220
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  		Figure 1. Meta-analysis of studies of the M235T polymorphism and CHD. Odds ratio is 1.08 (95% CI 1.0–1.16) when a fixed effect model was used.


Figure 2186220
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  		Figure 2. Studies of the M235T polymorphism grouped by study characteristics.


Figure 3186220
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  		Figure 3. Funnel plot of studies of the M235T polymorphism and CHD showing a possible excess of smaller studies with strikingly positive findings beyond the 95% CI (Begg test, P=0.04).


Figure 4186220
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  		Figure 4. Test publication bias of studies of the M235T polymorphism and CHD using Egger test.


Figure 5186220
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  		Figure 5. Trimmed and filled funnel plot of the M235T polymorphism and CHD. Hollow ovals are the actual studies included in the meta-analysis; solid squares, trimmed and filled studies required to achieve symmetry.

Association of T174M Variant With CHD
Marginal evidence of heterogeneity existed among the 16 available studies of the T174M variant and CHD (I2=44%; 95% CI, 0 to 69; P=0.03). Overall, the per-allele OR of the 174M variant for CHD was 1.07 (95% CI, 0.96 to 1.20; Figure 6), with corresponding results under dominant and recessive genetic models of 1.07 (95% CI, 0.93 to 1.22) and 1.32 (95% CI, 1.01 to 1.71), respectively. A funnel plot did not indicate the presence of publication bias in these studies (Begg test, P=0.56; Egger test, P=0.27) (plot available on request).


Figure 6186220
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  		Figure 6. Meta-analysis of studies of the T174M polymorphism and CHD. Odds ratio is 1.01 (95% CI 0.93–1.11) when a fixed effect model was used.

Haplotype Analyses
Haplotype analyses between M235T and T174M polymorphisms were performed in the 3 studies, involving 4710 cases and 13 770 controls.12,29,47 The pooled ORs of the 174T/235M, 174T/235T, and 174M/235T for CHD are 1.0 (95% CI, 0.95 to 1.07), 1.01 (95% CI, 0.95 to 1.08), and 0.97 (95% CI, 0.88 to 1.06), respectively (Table 2).


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  		TABLE 2. Meta-Analysis of Haplotype Combinations Between T174M and M235T Polymorphisms of AGT Gene and CHD Risk


*    Discussion
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 up arrowResults
 *Discussion
down arrowReferences
 
The present meta-analysis provides the most comprehensive assessment of AGT variants and CHD risk. Overall, a modest association existed between the M235T variant and CHD risk. However, this association became nonsignificant when the meta-analysis was restricted to larger studies, suggesting a publication bias. Meanwhile, our meta-analysis does not support an association between the M174T polymorphism and CHD risk. In addition, haplotypes analyses of the M235T and T174M alleles did not reveal any association between the combination of these alleles and risk of CHD.

Compared with the previous meta-analysis,53 the present study is much larger, with almost twice as many cases as the earlier meta-analysis. In addition, we assessed not only the association between the M235T polymorphism and CHD risk but also the association between the closely linked T174M polymorphism and CHD. Furthermore, we explored potential sources of heterogeneity across studies and the possibility of publication bias. Our results suggest an overestimation of the true genetic association by small studies, consistent with the phenomenon known as "winner’s curse."60,61

Several potential limitations of the present study should be considered. As with any meta-analysis of published results, the quality of our meta-analysis depends on that of individual studies. Ideally, we would like to pool individual-level data. However, this was not possible for the present study. In addition, the available data on the haplotype analyses of the M235T and T174M polymorphisms were sparse, so the summary estimates may not be reliable.

The RAS is a complex physiological system involved in multiple components and genes that define its activity and its regulatory actions (eg, on vascular growth or blood pressure); RAS system genes are highly polymorphic. The effects of any single polymorphisms and/or any single gene in the RAS system might have more limited impact on CHD than has so far been anticipated. The failure to demonstrate important associations between each of 2 AGT polymorphisms on CHD does not necessarily rule out the possibility that other variants or combination of alleles at multiple loci in the same genes could be relevant to CHD. Systematically screening the functional variants within the AGT gene and other related genes in the RAS system and functional experiments to confirm the causal variants and their epistatic interactions in the origin of CHD are needed. High-throughput genomic technologies should speed up the discovery of such variants, and further genetic association studies that involve very large numbers of cases and controls are needed to provide conclusive evidence on the effects of the AGT gene and other genes within the RAS system on risk of CHD.


*    Acknowledgments
 
Sources of Funding

This work was supported by grants from the National 973 and 863 programs, National Science Foundation of China, Shanghai Municipal Commission for Science and Technology, and the Ministry of Education, China

Disclosures

None.


*    References
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CLINICAL PERSPECTIVE

Angiotensinogen (AGT), a key protein in the renin-angiotensin system, plays an important role in cardiovascular hemostasis. Since the 1990s, many studies have examined the association between polymorphisms in the AGT gene and risk of coronary heart disease (CHD), but the results have been inconsistent. We performed a meta-analysis to assess the effects of 2 polymorphisms (M235T and T174M) of the AGT gene on the risk of CHD based on 43 original association studies, including a total of 13 478 CHD cases and 17 024 controls. In the combined analysis, the M235T polymorphism was associated with a small increased risk of CHD (11%). However, when the analyses were restricted to 4 larger studies (n>500 cases), the association became nonsignificant. Our analyses detected a publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the 174M variant also showed no significant overall association with CHD. Our findings indicate that neither M235T nor T174M on the AGT gene are associated with CHD risk. Additional very large-scale studies are warranted to provide conclusive evidence of the effects of the AGT gene and other genes within the renin-angiotensin system on the risk of CHD.


*    Footnotes
 
*The first 2 authors contributed equally to this work. Back




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