The Association of Angiotensin Converting Enzyme and Angiotensinogen Gene Polymorphism With Dilated Cardiomyopathy: A Systematic Review and Meta-Analysis

Abstract

Background:

Limited evidence exists for an association between dilated cardiomyopathy (DCM) and the angiotensin-converting enzyme (ACE) gene with an insertion/deletion (I/D) angiotensinogen (AGT) M235T gene polymorphism. A systematic review and meta-analysis were conducted to elucidate the role of ACE I/D and AGT M235T in the morbidity of DCM. This meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines for Abstracts.

Methods:

The PubMed, Embase, and Cochrane Library databases, as well as the Chinese Biomedical Literature Database, were reviewed to identify and collect all relevant studies. The association between ACE I/D, AGT M235T gene polymorphism, and DCM was estimated by pooling the odds ratio (OR) using the RevMan5.4.1 and Stata12.0 software.

Results:

A total of 27 eligible studies that explored the ACE I/D gene polymorphism in a healthy control group and the DCM patients were included in the present meta-analysis. A recessive genetic model was presented in the ACE I/D genotype. The pooled OR (DD vs. DI+II) following recessive genetic modelling was 1.37 (95% confidence interval (CI): 1.13, 1.66; p < 0.01). DCM patients tend to carry the DD genotype, indicating that the ACE I/D gene polymorphism might be associated with DCM. Similarly, seven studies were analyzed that presented a correlation between AGT M235T polymorphism and DCM morbidity. The OR (MT + TT vs. MM) value, according to a dominant genetic model, was 1.83 (95% CI: 0.90, 3.73; p > 0.05).

Conclusion:

The AGT M235T polymorphism was not significantly associated with DCM; however, the ACE I/D polymorphism was related to a risk of DCM.

Graphical abstract

Keywords

dilated cardiomyopathy / gene polymorphism / angiotensin converting enzyme / angiotensinogen / meta-analysis

1. Introduction

Dilated cardiomyopathy (DCM) is a myocardial disease characterized by the dilatation of either the left or both ventricles with impaired systolic function [1]. Despite recent advances in medical and surgical therapies, it remains an important cause of mortality and is a leading indication for heart transplantation. The prevalence of idiopathic DCM is approximately 1 in 250 individuals [2]. However, the causes of dilated cardiomyopathy are heterogeneous and unclear [3]. Nonfamilial DCM may have multifactorial etiologies resulting from an interaction between genetic and environmental factors. Several modifier genes also influence the DCM phenotype. Polymorphisms in the genes involved in the renin-angiotensin system (RAS) are associated with a higher risk of DCM [4, 5, 6].

In the RAS, angiotensinogen (AGT) is synthesized primarily by the liver and released into the blood, where it is cleaved by renin to generate angiotensin I. The latter is subsequently converted to angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is involved in cellular hypertrophy and proliferation [7], and thus regulates cardiac function, blood pressure, and electrolyte homeostasis [8]. The ACE gene is located on chromosome 17q23. An insertion/deletion (I/D) polymorphism (a 287-base-pair Alu repeat sequence) is usually present within intron 16 [9]. The AGT gene, located on chromosome 1q4, has an M235T polymorphism [10]. The ACE I/D gene and/or AGT M235T polymorphism are involved in cardiomyopathies [4, 5, 6, 11, 12, 13, 14, 15, 16, 17]. However, some studies could not establish any correlation between ACE I/D or the AGT M235T genotype and DCM [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]. Thus, the role of ACE I/D and AGT M235T genotype in the pathogenesis of nonfamilial DCM remains controversial. We decided to perform a meta-analysis to evaluate the effects of ACE I/D and AGT M235T gene polymorphism on the DCM phenotype. We reviewed case-control studies which explored the ACE I/D gene (OMIM number: 106180) and AGT M235T (OMIM number: *106150) gene polymorphism in healthy control and DCM patients, to determine the role of these two gene polymorphisms.

2. Methods

2.1 Search Strategy

A comprehensive search for relevant studies was conducted in PubMed, Embase, Cochrane Library, and the China Biology Medicine disc till February 2025. The review was prepared on the basis of published protocols [37, 38]. To find studies exploring the relationship between ACE I/D with DCM, the search words used in the PubMed database were: ACE or “angiotensin converting enzyme”, polymorphism or mutation, and “dilated cardiomyopathy or dilated cardiomyopathies”. Alternatively, ACE was replaced with “angiotensinogen” or “AGT” for studies related to angiotensinogen M235T genotype and DCM. Details of the Embase search strategy are described in Supplementary Material I. Language was not a limiting factor in our search.

2.2 Study Selection

Two authors independently reviewed all studies and collected the data using a standard information extraction approach following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [39, 40]. The studies included met with the following criteria: (1) a cohort study highlighting the ACE I/D allele polymorphism or AGT M235T gene polymorphism; (2) the case group involved DCM patients. (3) A healthy control group was included in all studies. The exclusion criteria were as follows: (1) reviews, comments, case reports, meta-analysis and animal experiments; (2) other studies in which neither ACE nor AGT gene polymorphism was explored in DCM or a control group in a DCM or control group.

2.3 Data Extraction and Risk of Bias

The following data were collected: the first author of the studies, year of publication, genotypes of patients and controls, p-values to calculate Hardy-Weinberg equilibrium (HWE) in the control group, the source of control subjects, and diagnosis methods or criteria in DCM patients.

The quality of studies was independently assessed by two authors using a revised bias assessment score (Supplementary Material II) [41]. Total scores ranged from 0 (worst) to 13 (best). Any dissension was resolved by discussion.

2.4 Statistical Analysis

All data for statistical analysis were obtained from the published paper or meeting abstracts. RevMan Software 5.4.1 (Cochrane Collaboration, https://www.cochrane.org/products-and-services/review-writing-software) was used for pooling the odds ratio (OR) in the meta-analysis. Meta-regression and calculation of genetic models were performed with Stata 12.0 software (StataCorp LP, College Station, TX, USA). The most appropriate genetic models were calculated following protocols described previously [41, 42]. Continuity correction by adding 1 into the 0 genotype was applied. For ACE I/D gene polymorphism, a recessive genetic model was used. For the role of AGT M235T genotype in DCM, a dominant model was used. Meta-regression was used to explore potential sources of heterogeneity. A p-value less than 0.10 and I² greater than 50% were considered to be significant for statistical heterogeneity. The random-effect model was used in the analysis [43, 44]. Sensitivity analysis was also performed to test the robustness of the results by excluding studies that deviated from HWE. In addition, a subgroup analysis to determine the origin of the patients was also performed. Begg’s test, Egger’s test and funnel plots were used to assess and avoid any publication bias.

3. Results

3.1 Search Results

A total of 242 studies were retrieved for ACE gene polymorphism and 26 studies for AGT gene polymorphism from the databases. Among them, 29 studies were included in the analysis. Of these, 27 studies [4, 5, 6, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36] were included in the meta-analysis to show an association between ACE I/D gene polymorphism and DCM (Fig. 1a); 7 studies [11, 15, 19, 20, 26, 28, 30] correlated AGT M235T gene polymorphism and DCM (Fig. 1b). Among these, five studies [11, 19, 20, 28, 30] were included in both the ACE I/D and AGT M235T gene polymorphism analysis. Fig. 1 shows the flow diagram of the criteria used in the study selection. Table 1a (Ref. [4, 5, 6, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]) and Table 1b (Ref. [11, 15, 19, 20, 26, 28, 30]) list the selected studies and the main characteristics in the control and DCM Group. The quality of the selected studies is shown in Supplementary Material III.

3.2 HWE and the Minor Allele Frequency

Calculated HWE values in the control group are shown in Table 1a and Table 1b. Table 2a (Ref. [4, 5, 6, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]) and Table 2b (Ref. [11, 15, 19, 20, 26, 28, 30]) represent the ACE I/D and AGT M236T gene polymorphism (minor allele). In the studies associating ACE I/D gene polymorphism with DCM, the minor allele in the control group (D allele) had an allele frequency of 48.86% (95% CI: 44.25%, 53.47%). The minor allele in the control group for the AGT genotype was the T allele with a frequency of 49.04% (95% CI: 24.49%, 73.59%).

3.3 Meta-Analysis of the Association Between Genotype and DCM Phenotype

The 27 eligible studies, connecting ACE I/D allele polymorphism with the risk of DCM, included 2460 medical cases and 3857 healthy subjects as the control for the meta-analysis. The recessive genetic model was selected for the case-control studies, in which the comparison of DD vs. DI+II was made. The pooled OR as per the regressive genetic model was 1.37 with the random-effect model (95% CI: 1.13, 1.66; p 0.01, I² = 57%; Fig. 2a). These results suggest that the frequency of the DD genotype was higher in DCM patients than that seen in the control group. After excluding three studies that had deviated from HWE [4, 24, 31], OR (DD vs. DI+II) was found to be 1.38 (95% CI: 1.14, 1.68, p 0.01, I² = 56%, Supplementary Fig. 1. Sensitivity analysis indicated that the statistical result did not vary even after excluding any single study. Since the quality scores in studies published before 2000 might be different compared to post-2010 studies, reflecting advancements in genotyping and study design, we performed the meta-analysis with the random-effect model after excluding the older studies before 2000, and the pooled OR is 1.41 (95% CI: 1.10, 1.80, Supplementary Fig. 2). The pooled OR is 1.32 (95% CI: 1.07, 1.65) if the studies after 2010 are excluded (Supplementary Fig. 3). These results indicate that the results of the meta-analysis are robust. Sub-group analysis revealed that the pooled OR (DD vs. DI+II) was statistically significant in the Asian and in the European/USA population (p 0.05) but not in the African population. Publication bias was verified by Begg’s test and Egger’s test (p > 0.05; Fig. 2b). Meta-regression analysis indicated that neither the time of publication nor the origin of the population significantly contributed to the heterogeneity in ACE I/D gene polymorphism (p > 0.05).

The seven eligible studies, associating AGT M235T gene polymorphism with DCM, included 1086 DCM patients and 1346 healthy controls. A dominant model (genetic model) was selected, and the comparison of MT+TT vs. MM was made for the meta-analysis.

The pooled OR was 1.83 (Fig. 3a: 95% CI: 0.90, 3.73; p > 0.05, I² = 86.1%, Fig. 3a), indicating that AGT M235T gene polymorphism is not significantly attributed to DCM. Sensitivity analysis indicated that the exclusion of any study did not significantly change the statistical result. The pooled OR did not significantly change after excluding the studies that did not follow HWE [15, 20] (OR = 1.58, 95% CI: 0.74, 3.37, p > 0.05, Supplementary Fig. 4). These results indicated that the pooled OR value is credible. Egger’s test and Begg’s test (p > 0.05; Fig. 3b) indicated that there is no significant publication bias. Meta-regression analysis indicated that neither time of publication nor origin of the population was the main source of heterogeneity (p > 0.05).

4. Discussion

Our meta-analysis revealed that ACE DD genotype frequency was higher in DCM patients, indicating that ACE I/D gene polymorphism might be associated with the risk of DCM. The subgroup analysis indicated that DD genotype frequency is higher in the Asian and European/USA population. However, it is not significant in Africans. There are just three studies from the African population. Therefore, this lack of association may be due to the small number of studies involving African populations, which limits the statistical power.

DCM is a disease of unknown etiology characterized by ventricular dilation and impaired systolic function [3]. It clinically manifests in heart pump failure or sudden death [45] and is a major indication for heart transplantation [19].

Mutations in genes encoding sarcomeric structural proteins are known contributors to DCM [46]. However, clinical evaluation of families with DCM often reveals the absence of disease in individuals carrying these mutations [2].

The number of rare variants implicated in DCM in the Exome Variant Server (EVS) database was at least double than reported in genetic studies [2]. In addition, the extent of genetic defects varies even among people with the same mutation within the same family. A fixed predictable genotype-phenotype correlation for a specific mutation has not been reported [3]. It has been proposed that clinical heterogeneity in DCM patients is a result of multiple factors, including age, disease-causing gene mutations, environmental effects, and genetic modifiers [47].

Several genes, including those encoding the components of the RAS, are considered potential modifiers in DCM [5]. RAS is a major regulator of cardiovascular and renal functions, including sodium extraction/reabsorption and water balance [26]. Thus, the systemic or local cardiovascular RAS system contributes to the pathophysiology of various cardiovascular diseases and may play an autocrine or paracrine role in cardiac remodeling and fibrosis [48, 49].

In RAS, renin cleaves a terminal decapeptide from angiotensinogen to form angiotensin I [50], which is further catalyzed (enzymatic removal of a dipeptide) into angiotensin II by ACE. ACE is present on the surface of vascular endothelial cells as a membrane-bound enzyme and circulates in plasma. Cloning of the ACE gene revealed a 287 base pair (bp) Alu repeat sequence with an I/D polymorphism in intron 16 resulting in three genotypes: II, ID, and DD [51, 52]. This polymorphism was strongly associated with increased expression of ACE and high levels of angiotensin II. The mean plasma ACE level in individuals with the DD genotype was almost double that of the II genotype, while subjects with ID genotype had intermediate levels [9]. The modulating effect of the DD genotype on DCM is due to increased ACE activity [6].

Tan and coworkers [53] reported that both endogenous and exogenous angiotensin II lead to myocyte necrosis, abnormal sarcolem permeability, myocytolysis, fibroblast proliferation, and subsequent replacement fibrosis in vivo. In addition, angiotensin II stimulation in cardiac fibroblasts of adult rats in vitro results in a higher synthesis of extracellular matrix proteins [54]. This increased extracellular matrix synthesis is a key feature of cardiac fibrosis, a condition where the heart tissue becomes stiff and less elastic [55]. Subsequent myocardial remodeling and increased arterial stiffness may result due to the reduction in left ventricular ejection fraction [6]. Elevated angiotensin II levels are associated with an increased mortality rate in heart failure patients [56].

Cardiac collagen deposition in rats may be regulated by RAS activity [57], and this accumulation can be prevented by non-hypotensive doses of ACE inhibitors. Candy and coworkers [21] asserted that the D allele is associated with worsening of left ventricular (LV) systolic function as well as an increase in left ventricular cavity size that occurs in idiopathic DCM. DD genotype is an independent predictor of higher mortality, LV systolic performance, as well as cavity size in idiopathic DCM [21]. Clinical trials have underscored the therapeutic importance of ACE inhibitors in heart failure [58]. Experimental data in animals and preliminary studies in humans have demonstrated that early administration of captopril, an ACE inhibitor, attenuated progressive LV dilatation [59].

In the present study, we did not confirm an association between the AGT M235T polymorphism and DCM. It is reported that the AGT haplotype, which carries the A (-6) G variation in the promoter, and M235T polymorphism, is associated with higher plasma AGT levels [26, 60]. Bloem and colleagues [61] also found that the T235 allele frequency was higher in black compared to white children, which correlated with the 19% higher mean angiotensin levels in blacks than in whites. Polymorphism of the AGT gene is thus race-specific. It is reported that there was almost complete linkage disequilibrium of G (-6) A with the M235T of AGT gene [26]. The null finding for AGT M235T may reflect low statistical power (small sample size, n = 7 studies, among them, one study did not take part in the pool OR due to the number of MM genotype was zero in both the control and DCM group) or population-specific linkage disequilibrium (e.g., AGT haplotypes with promoter). Future studies should prioritize haplotype analysis and larger sample sizes for AGT-related endpoints.

Our result is distinct from a previous genome-wide association study (GWAS) on DCM as we have identified an association between ACE I/D single nucleotide polymorphism and DCM [62]. To our knowledge, the criterion of assessing statistical significance in GWAS is stricter than in general comparative studies.

5. Limitations

There are some limitations in our meta-analysis. First, the studies included are smaller, especially studies associating AGT M235T with DCM (only 7 studies), and ACE I/D gene polymorphism in Africa, which may lack statistical power to detect true associations. Second, several studies in this meta-analysis reported only a few patient cases. Finally, the qualities of some studies were not satisfactory; for example, three studies deviated from HWE for ACE I/D gene polymorphism. In addition, DCM diagnosis across studies used WHO criteria, echocardiography, or a combination, which may introduce heterogeneity. Standardizing diagnostic thresholds (e.g., left ventricular ejection fraction cutoffs) in future could improve consistency. In the end, the review was not registered. All of these limitations may have affected the results of the present study. Further investigations are required to explain the effect of AGT M235T and ACE I/D polymorphisms in the pathogenesis of DCM.

6. Conclusion

In conclusion, despite the above limitations, the present study has suggested that ACE I/D, but not AGT M235T gene polymorphism, might be a risk factor for DCM. Additional large-scaled and more rigorous case-control studies are needed to further confirm the role of ACE I/D and AGT M235T polymorphisms in DCM.

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Funding

National Natural Science Foundation of China(32171182)

Sichuan Provincial Natural Science Foundation(2024NSFSC0553)

Development and Regeneration Key Laboratory of Sichuan Province(23LHNBZZD02)