IMR Press / RCM / Volume 26 / Issue 10 / DOI: 10.31083/RCM39763
Cite this article
Nanoparticles: Properties, applications and toxicities
4
Downloads
38
Views
Submit to RCM
Review for RCM
Apply for Special Issue
  • Academic Editor
    Francesco Pelliccia
Chapters
Figures
References
Abstract
Keywords
1. Introduction
2. Methods
3. Results
4. Discussion
5. Limitations
6. Conclusion
Availability of Data and Materials
Author Contributions
Ethics Approval and Consent to Participate
Funding
Conflict of Interest
Associated Data
References
Open Access Systematic Review
The Association of Angiotensin Converting Enzyme and Angiotensinogen Gene Polymorphism With Dilated Cardiomyopathy: A Systematic Review and Meta-Analysis
Songbai Du1, Ningting Jiang2, Yilin He2, Zhiming Li1, Chang Liu2, Rong Luo2,*
Show Less
Affiliation
1 Department of Cardiology, Nanbu County People's Hospital, 637300 Nanchong, Sichuan, China
2 Institute of Geriatric Cardiovascular Disease, Chengdu Medical College, 610500 Chengdu, Sichuan, China
*Correspondence: luorong77@126.com (Rong Luo)
Rev. Cardiovasc. Med. 2025, 26(10), 39763; https://doi.org/10.31083/RCM39763
Submitted: 16 April 2025 | Revised: 3 July 2025 | Accepted: 22 July 2025 | Published: 21 October 2025
Copyright: © 2025 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
PDF
Brower Figures
Cite
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.

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.

Fig. 1.

Flow diagram highlighting the criteria for selection of the studies. (a) ACE I/D flow diagram. (b) AGT flow diagram. DCM, dilated cardiomyopathy; ACE, angiotensin converting enzyme; AGT, angiotensinogen; I/D, insertion/deletion; CBM, the China Biology Medicine disc.

Table 1a. Characteristics of eligible studies associating ACE I/D gene polymorphism and DCM.
First author, Year Ethnic DCM Control HWE in control p value Control subjects Diagnosis methods/criteria in DCM patients
Genotypes Genotypes
N II ID DD N II ID DD
Kose et al. 2014 [22] Turkey 36 8 17 11 104 16 47 41 0.6780 Healthy subjects Echocardiography
Kong et al. 2012 [34] Han Chinese 101 21 48 32 105 30 53 22 0.8744 Healthy individuals WHO/ISFC diagnostic criteria of DCM in 1995
Mahjoub et al. 2010 [5] Tunisia 76 12 38 26 151 46 83 22 0.1162 Age, sex and ethnicity matched controls without any previous history of cardiovascular disorders Criteria provided by the World Health Organization.
Shan et al. 2001 [18] Chinese 83 27 25 31 155 50 80 25 0.4564 Healthy individuals WHO/ISFC diagnostic criteria of DCM in 1995, echocardiography
Zou et al. 2003 [17] Chinese 43 12 18 13 53 28 20 5 0.6095 Age and gender matched healthy individual and blood donor WHO/ISFC diagnostic criteria of DCM in 1995, echocardiography
Wu et al. 2002 [35] Chinese 43 14 22 7 63 23 28 12 0.5092 Healthy individuals WHO/ISFC diagnostic criteria of DCM in 1995, echocardiography
Küçükarabaci et al. 2008 [23] Turkey 29 5 18 6 20 7 9 4 0.7229 Healthy subjects Echocardiography
Rai et al. 2008 [6] India 51 8 33 10 164 47 87 30 0.3532 Healthy, age, sex, and ethnicity matched controls without any previous history of cardiovascular disorders Echocardiography
Jurkovicova et al. 2007 [19] Caucasian population of Slovakia 110 21 50 39 156 38 78 40 0.9984 Healthy control subjects matched to patients by gender and age Not defined
Covolo et al. 2003 [36] Italy 122 17 62 43 230 39 105 86 0.4744 Born in Italy, had no clinical symptoms or signs suggesting the presence of HF, and no history of CHD or IDC Echocardiography
Tiago et al. 2002 [20] South Africa 157 26 60 71 225 18 105 102 0.2050 Healthy, unrelated Black South Africans were recruited from the general population of surrounding districts Echocardiography
Tiret et al. 2000 [28] France 422 94 200 128 387 71 190 126 0.9662 Age matched French population without clinical history of cardiovascular disease or insulindependent diabetes Radionucleotide angiography or echocardiography
Straburzynska-Migaj 2005 [32] Poland 52 14 19 19 110 28 48 34 0.1910 Healthy pregnant women Echocardiography
Candy et al. 1999 [21] Black South Africans 171 27 72 72 106 13 46 47 0.7376 Age matched, unrelated black South Africans free of cardiovascular disease Echocardiography and radionuclide ventriculography
Vancura et al. 1999 [29] Czech 90 27 33 30 287 70 146 71 0.7677 Residents from 1 district in central Bohemia Not defined
Yamada et al. 1997 [30] Japanese 88 36 35 17 122 50 55 17 0.7640 Healthy individuals Echocardiography, coronary angiography and left ventriculography
Sanderson et al. 1996 [27] Chinese 51 20 25 6 183 71 88 24 0.6882 Healthy subjects and patients without heart disease The criteria set by the World Health Organization, Echocardiography, and cardiac catheterization
Montgomery et al. 1995 [25] United Kingdom 99 18 50 31 364 84 168 112 0.1729 Local general practice group The criteria recommended by the WorldHealth Organization, Echocardiography
Raynolds et al. 1993 [14] USA 112 22 50 40 89 20 50 19 0.2431 Actual or prospective heart donors and healthy volunteers with normal ECG and echocardiographic studies Echocardiogram
Ozhan et al. 2004 [31] Turkey 35 4 17 14 88 11 28 49 0.0411 Healthy unrelated age-and sex-matched subjects Transthoracic echocardiogram
Kurbanov et al. 2014 [24] Uzbekistan 102 33 45 24 60 34 14 12 0.0004 Healthy subjects The diagnostic criteria for DCM (WHO, 1995), echocardiography
Harn et al. 1995 [4] Chinese 35 2 13 20 35 2 24 9 0.0112 Patients with normal donor-screening echocardiograms and normal coronary arteriograms Echocardiography
Rani et al. 2017 [11] India 177 15 120 42 200 72 86 42 0.0891 Healthy, ethnicity-matched unrelated subjects without any family history of heart disease, hypertension, diabetes or any other chronic ailments Echocardiography
Schmidt et al. 1996 [33] Austria 14 4 7 3 95 21 38 36 0.0801 Healthy control group Ultrasonography
Chen et al. 2017 [16] Chinese 64 17 29 18 120 51 57 12 0.4957 Healthy individuals Diagnostic criteria of Chinese Society of Cardiology
Goncalvesova et al. 2005 [12] Slovak 70 15 29 26 103 28 51 24 0.9336 General Slovak population Echocardiography
Berg et al. 2012 [13] Bashkortostan 27 10 9 8 82 32 41 9 0.4394 Healthy people, age, gender and ethnicity matched, without chronic diseases as well as without pathology of cardiovascular system in the anamnesis WHO classification criteria, echocardiogram, and coronarography

ACE, angiotensin-converting enzyme; I/D, insertion/deletion; DCM, dilated cardiomyopathy; HWE, Hardy-Weinberg equilibrium; WHO/ISFC, World Health Organization/International Society of Forensic Genetics; CHD, coronary Heart Disease; IDC, idiopathic dilated cardiomyopathy; ECG, electrocardiograph.

Table 1b. Characteristics of eligible studies correlating AGT M235T gene polymorphism with DCM.
First author, Year Ethnic DCM Control HWE in control p value Control subjects Diagnosis methods in DCM patients
Genotypes Genotypes
N MM MT TT N MM MT TT
Jurkovicova et al. 2007 [19] Caucasian population of Slovakia 110 31 51 28 156 62 69 25 0.4339 Healthy control subjects matched to patients by gender and age Not defined
Tiago et al. 2002 [20] South Africa 157 0 55 102 225 0 58 167 0.0265 Healthy, unrelated Black South Africans were recruited from the general population of surrounding districts Echocardiography
Tiret et al. 2000 [28] France 428 157 200 71 398 131 195 72 0.9695 Age matched French population without clinical history of cardiovascular disease or insulin-dependent diabetes Radionucleotide angiography or echocardiography
Pávková Goldbergová et al. 2011 [26] Czech Republic 91 23 55 13 203 65 101 37 0.8377 Not define Not defined
Yamada et al. 1997 [30] Japan 88 3 29 56 122 2 44 76 0.1190 Healthy individuals Echocardiography, left ventriculography, and coronary angiography
Rani et al. 2017 [11] India 177 15 120 42 200 72 86 42 0.0891 Healthy, ethnicity-matched unrelated subjects without any family history of heart disease, hypertension, diabetes or any other chronic ailments Echocardiography
Ullah et al. 2019 [15] Pakistan 35 20 0 15 42 38 0 4 0.0000 Ethnically matched healthy controls without any history for heart abnormality, hypertension and diabetes Not defined

DCM, dilated cardiomyopathy; HWE, Hardy-Weinberg equilibrium; AGT, angiotensinogen.

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%).

Table 2a. Estimation of the minor allele (D) frequency in control groups for ACE I/D genotype.
First Author, Year D allele frequency Total frequency Allele D allele percent (%)
Kong et al. 2012 [34] 97 210 46.1905
Shan et al. 2001 [18] 130 310 41.9355
Zou et al. 2003 [17] 30 106 28.3019
Wu et al. 2002 [35] 52 126 41.2698
Kose et al. 2014 [22] 129 208 62.0192
Mahjoub et al. 2010 [5] 127 302 42.0530
Küçükarabaci et al. 2008 [23] 17 40 42.5000
Rai et al. 2008 [6] 147 328 44.8171
Jurkovicova et al. 2007 [19] 158 312 50.6410
Covolo et al. 2003 [36] 277 460 60.2174
Tiago et al. 2002 [20] 309 450 68.6667
Tiret et al. 2000 [28] 442 774 57.1059
Straburzynska-Migaj et al. 2005 [32] 116 220 52.7273
Candy et al. 1999 [21] 140 212 66.0377
Vancura et al. 1999 [29] 288 574 50.1742
Yamada et al. 1997 [30] 89 244 36.4754
Sanderson et al. 1996 [27] 136 366 37.1585
Montgomery et al. 1995 [25] 392 728 53.8462
Raynolds et al. 1993 [14] 88 178 49.4382
Ozhan et al. 2004 [31] 126 176 71.5909
Kurbanov et al. 2014 [24] 38 120 31.6667
Harn et al. 1995 [4] 42 70 60.0000
Rani et al. 2017 [11] 170 400 42.5000
Schmidt et al. 1996 [33] 110 190 57.8947
Chen et al. 2017 [16] 81 240 33.7500
Goncalvesova et al. 2005 [12] 99 206 45.0583
Berg et al. 2012 [13] 59 164 35.9756

Note, Pooled D allele prevalence (%): 48.63 (95% CI: 44.05, 53.20). ACE, angiotensin converting enzyme; I/D, insertion/deletion.

Table 2b. Estimation of the minor allele (T) frequency in control groups for AGT M235T genotype.
First Author, Year T allele frequency Total frequency Allele T allele percent (%)
Jurkovicova et al. 2007 [19] 119 312 38.1410
Tiago et al. 2002 [20] 392 450 87.1111
Tiret et al. 2000 [28] 339 796 42.5879
Pávková Goldbergová et al. 2011 [26] 175 406 43.1034
Yamada et al. 1997 [30] 196 244 80.3279
Rani et al. 2017 [11] 170 400 42.5000
Ullah et al. 2019 [15] 8 84 9.5238

Note, Pooled T allele prevalence (%): 49.044 (95% CI: 24.49, 73.59). AGT, angiotensinogen.

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).

Fig. 2.

Forest plot and funnel plot of meta-analysis about ACE I/D gene polymorphism in association with risk of DCM phenotype. (a) Forest plot. (b) Funnel plot. The pooled OR in (a) indicated the OR of DD vs. DI+II genotypes. The pooled OR was 1.37 (95% CI: 1.13, 1.66; p < 0.01). The Begg’s test and Egger’s test indicated that there was no obvious publication bias. ACE, angiotensin converting enzyme; I/D, insertion/deletion; DCM, dilated cardiomyopathy.

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).

Fig. 3.

Forest plot and funnel plot of the meta-analysis correlating AGT M235T gene polymorphism with the development of DCM. (a) Forest plot. (b) Funnel plot. OR in (a) indicated the OR of MT+TT vs. MM genotypes. The pooled OR was 1.83 (95% CI: 0.90, 3.73; p > 0.05). The Begg’s test and Egger’s test indicated that there was no significant publication bias. AGT, angiotensinogen; DCM, dilated cardiomyopathy.

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.

Abbreviations

DCM, dilated cardiomyopathy; ACE, angiotensin converting enzyme; AGT, angiotensinogen; RAS, renin-angiotensin system; HCM, hypertrophic cardiomyopathy; EVS database, Exome Variant Server database.
Availability of Data and Materials

Data involved in statistics are presented in Table 1a and Table 1b. For further information, please contact the corresponding author.

Author Contributions

SD and NJ, Data collecting and formal analysis; YH and ZL, checking the data and analysis; CL, writing-review & editing the manuscript; RL, Conceptualizing and writing-original draft, funding acquisition. All authors contributed to the conception and editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This study was supported by grant from the National Natural Science Foundation of China (No.32171182); the Sichuan Provincial Natural Science Foundation (No. 2024NSFSC0553); Development and Regeneration Key Laboratory of Sichuan Province (No.23LHNBZZD02).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Material

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM39763.

References
[1]
Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996; 93: 841–842. https://doi.org/10.1161/01.cir.93.5.841.
[2]
Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nature Reviews. Cardiology. 2013; 10: 531–547. https://doi.org/10.1038/nrcardio.2013.105.
[3]
Murphy RT, Starling RC. Genetics and cardiomyopathy: where are we now? Cleveland Clinic Journal of Medicine. 2005; 72: 465–483.
[4]
Harn HJ, Chang CY, Ho LI, Liu CA, Jeng JR, Lin FG, et al. Evidence that polymorphism of the angiotensin I converting enzyme gene may be related to idiopathic dilated cardiomyopathy in the Chinese population. Biochemistry and Molecular Biology International. 1995; 35: 1175–1181.
[5]
Mahjoub S, Mehri S, Bousaada R, Ouarda F, Zaroui A, Zouari B, et al. Association of ACE I/D polymorphism in Tunisian patients with dilated cardiomyopathy. Journal of the Renin-angiotensin-aldosterone System: JRAAS. 2010; 11: 187–191. https://doi.org/10.1177/1470320310368874.
[6]
Rai TS, Dhandapany PS, Ahluwalia TS, Bhardwaj M, Bahl A, Talwar KK, et al. ACE I/D polymorphism in Indian patients with hypertrophic cardiomyopathy and dilated cardiomyopathy. Molecular and Cellular Biochemistry. 2008; 311: 67–72. https://doi.org/10.1007/s11010-007-9695-z.
[7]
Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circulation Research. 1993; 73: 413–423. https://doi.org/10.1161/01.res.73.3.413.
[8]
Griendling KK, Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulation. 1993; 87: 1816–1828. https://doi.org/10.1161/01.cir.87.6.1816.
[9]
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. The Journal of Clinical Investigation. 1990; 86: 1343–1346. https://doi.org/10.1172/JCI114844.
[10]
Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992; 71: 169–180. https://doi.org/10.1016/0092-8674(92)90275-h.
[11]
Rani B, Kumar A, Bahl A, Sharma R, Prasad R, Khullar M. Renin-angiotensin system gene polymorphisms as potential modifiers of hypertrophic and dilated cardiomyopathy phenotypes. Molecular and Cellular Biochemistry. 2017; 427: 1–11. https://doi.org/10.1007/s11010-016-2891-y.
[12]
Goncalvesova E, Palacka P, Sedlakova B, Jurkovicova D, Krizanova O. Polymorphism of the ACE gene in patients with chronic heart failure due to dilated cardiomyopathy. Cardiol. 2005; 14: 296–300. (In Slovak)
[13]
Berg AR, Chepurnaya AN, Karimov DO, Viktorova TV, Nikulicheva VI, Safuanova GS. Analysis of gene polymorphic variants of angiotensinconverting enzyme, glutathione S‐transferase in cardiomyopathy sick patients. Russian Open Medical Journal. 2012; 1: 0301.
[14]
Raynolds MV, Bristow MR, Bush EW, Abraham WT, Lowes BD, Zisman LS, et al. Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet (London, England). 1993; 342: 1073–1075. https://doi.org/10.1016/0140-6736(93)92061-w.
[15]
Ullah MI, Aisha NM, Shakil M, Samreen T, Idrees A, Hussain S, et al. Genetic Association of AGT Polymorphism in patients with Dilated Cardiomyopathy from Punjabi population of Pakistan. Pakistan Journal of Medical and Health Sciences. 2019; 13: 157–160.
[16]
Chen W, Zhao T, Chen D, Liu Y, Xiong M, Gui Q. Relationship between ACE gene polymorphism and idiopathic dilated cardiomyopathy in patients of south China. Shandong Yiyao. 2017; 57: 24–26. (In Chinese)
[17]
Zou D, Yuan F, Guo J, Zang B, Wu K. Relationship between hypertrophic cardiomyopathy and dilated cardiomyopathy and angiotensin converting enzyme gene polymorphism. Journal of China Medical University. 2003; 32: 162–164. (In Chinese)
[18]
Shan J, Li Z, Shi Y, Fu G. Association of the genetic polymorphism of angiotensin-converting enzyme and idiopathic dilated cardiomyopathy. Chinese Journal of Cardiology. 2001; 29: 286–288. https://doi.org/10.3760/j:issn:0253-3758.2001.05.015. (In Chinese)
[19]
Jurkovicova D, Sedlakova B, Riecansky I, Goncalvesova E, Penesova A, Kvetnansky R, et al. Cardiovascular diseases and molecular variants of the renin-angiotensin system components in Slovak population. General Physiology and Biophysics. 2007; 26: 27–32.
[20]
Tiago AD, Badenhorst D, Skudicky D, Woodiwiss AJ, Candy GP, Brooksbank R, et al. An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy. Cardiovascular Research. 2002; 54: 584–589. https://doi.org/10.1016/s0008-6363(02)00281-x.
[21]
Candy GP, Skudicky D, Mueller UK, Woodiwiss AJ, Sliwa K, Luker F, et al. Association of left ventricular systolic performance and cavity size with angiotensin-converting enzyme genotype in idiopathic dilated cardiomyopathy. The American Journal of Cardiology. 1999; 83: 740–744. https://doi.org/10.1016/s0002-9149(98)00981-3.
[22]
Kose M, Akpinar TS, Bakkaloglu OK, Tufan A, Sumnu A, Emet S, et al. Association of genetic polymorphisms with endothelial dysfunction in chronic heart failure. European Review for Medical and Pharmacological Sciences. 2014; 18: 1755–1761.
[23]
Küçükarabaci B, Birdane A, Güneş HV, Ata N, Değirmenci I, Başaran A, et al. Association between angiotensin converting enzyme (ACE) gene I/D polymorphism frequency and plasma ACE concentration in patients with idiopathic dilated cardiomyopathy. Anadolu Kardiyoloji Dergisi: AKD = the Anatolian Journal of Cardiology. 2008; 8: 65–66.
[24]
Kurbanov RD, Kurbanov NA, Abdullayev TA. Angiotensin- converting enzyme gene polymorphism, the clinical course and the Structural and functional state of the heart at the Uzbek patients with dilated cardiomyopathy. The Journal of Eurasian Cardiology. 2014; 2: 63–70. https://doi.org/10.38109/2225-1685-2014-2-63-70. (In Russian)
[25]
Montgomery HE, Keeling PJ, Goldman JH, Humphries SE, Talmud PJ, McKenna WJ. Lack of association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and idiopathic dilated cardiomyopathy. Journal of the American College of Cardiology. 1995; 25: 1627–1631. https://doi.org/10.1016/0735-1097(95)00109-h.
[26]
Pávková Goldbergová M, Spinarová L, Spinar J, Pařenica J, Sišková L, Groch L, et al. Difference in angiotensinogen haplotype frequencies between chronic heart failure and advanced atherosclerosis patients - new prognostic factor? Physiological Research. 2011; 60: 55–64. https://doi.org/10.33549/physiolres.931976.
[27]
Sanderson JE, Young RP, Yu CM, Chan S, Critchley JA, Woo KS. Lack of association between insertion/deletion polymorphism of the angiotensin-converting enzyme gene and end-stage heart failure due to ischemic or idiopathic dilate cardiomyopathy in the Chinese. The American Journal of Cardiology. 1996; 77: 1008–1010. https://doi.org/10.1016/s0002-9149(97)89160-6.
[28]
Tiret L, Mallet C, Poirier O, Nicaud V, Millaire A, Bouhour JB, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. Journal of the American College of Cardiology. 2000; 35: 29–35. https://doi.org/10.1016/s0735-1097(99)00522-7.
[29]
Vancura V, Hubácek J, Málek I, Gebauerová M, Pitha J, Dorazilová Z, et al. Does angiotensin-converting enzyme polymorphism influence the clinical manifestation and progression of heart failure in patients with dilated cardiomyopathy? The American Journal of Cardiology. 1999; 83: 461–2, A10. https://doi.org/10.1016/s0002-9149(98)00889-3.
[30]
Yamada Y, Ichihara S, Fujimura T, Yokota M. Lack of association of polymorphisms of the angiotensin converting enzyme and angiotensinogen genes with nonfamilial hypertrophic or dilated cardiomyopathy. American Journal of Hypertension. 1997; 10: 921–928. https://doi.org/10.1016/s0895-7061(97)00112-x.
[31]
Ozhan H, Zungur M, Yazici M, Akdemir R, Gunduz H, Erbilen E, et al. Angiotensin-converting enzyme, angiotensin II receptor, apolipoprotein E and endothelial constitutive nitric oxide synthase gene polymorphisms in dilated cardiomyopathy. Turk Kardiyoloji Dernegi Arsivi. 2004; 32: 295–301.
[32]
Straburzynska-Migaj E, Ochotny R, Chmara E, Jablecka A, Straburzynska-Lupa A, Cieslinski A. Angiotensin converting enzyme gene polymorphism in patients with heart failure. Folia Cardiology Journal. 2005; 12: 364–369. (In Polish)
[33]
Schmidt A, Kiener HP, Barnas U, Arias I, Illievich A, Auinger M, et al. Angiotensin-converting enzyme polymorphism in patients with terminal renal failure. Journal of the American Society of Nephrology: JASN. 1996; 7: 314–317. https://doi.org/10.1681/ASN.V72314.
[34]
Kong Y, Yun M, Wang G. Correlaltion of polymorphism of the ACE gene with dilated cardiomyopathy in Han nationality. China Tropical Medicine. 2012; 12: 623–624. (In Chinese)
[35]
Wu G, Ma A, Li Z, Geng T. Study of the association between the I/D polymorphism of the ACE gene , A/G polymorphism of the heart chymase gene and idiopathic dilated cardiomyopathy. Journal of Clinical Cardiology. 2002; 18: 100–103. https://doi.org/10.3969/j.issn.1001-1439.2002.03.003. (In Chinese)
[36]
Covolo L, Gelatti U, Metra M, Donato F, Nodari S, Pezzali N, et al. Angiotensin-converting-enzyme gene polymorphism and heart failure: a case-control study. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals. 2003; 8: 429–436. https://doi.org/10.1080/13547500310001599052.
[37]
Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Statistics in Medicine. 2005; 24: 1291–1306. https://doi.org/10.1002/sim.2010.
[38]
Tang ZY, Ye ZM, Zheng JH, Jiang F, Tang YM. A comprehensive evaluation of single nucleotide polymorphisms associated with atrophic gastritis risk: A protocol for systematic review and network meta-analysis. Medicine. 2020; 99: e20677. https://doi.org/10.1097/MD.0000000000020677.
[39]
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology. 2009; 62: e1–e34. https://doi.org/10.1016/j.jclinepi.2009.06.006.
[40]
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine. 2009; 6: e1000100. https://doi.org/10.1371/journal.pmed.1000100.
[41]
Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between beta2-adrenoceptor polymorphisms and asthma: a HuGE review. American Journal of Epidemiology. 2005; 162: 201–211. https://doi.org/10.1093/aje/kwi184.
[42]
Luo R, Li X, Fan X, Yuan W, Wu X. Association of tumor necrosis factor-α gene G-308A polymorphism with dilated cardiomyopathy: a meta-analysis. DNA and Cell Biology. 2013; 32: 130–137. https://doi.org/10.1089/dna.2012.1911.
[43]
Gashaw T, Yadeta TA, Weldegebreal F, Demissie L, Jambo A, Assefa N. The global prevalence of antibiotic self-medication among the adult population: systematic review and meta-analysis. Systematic Reviews. 2025; 14: 49. https://doi.org/10.1186/s13643-025-02783-6.
[44]
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4. Cochrane. 2023. Available at: https://training.cochrane.org/handbook (Accessed: 21 February 2025).
[45]
Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation. 1995; 91: 532–540. https://doi.org/10.1161/01.cir.91.2.532.
[46]
McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. The Journal of Clinical Investigation. 2013; 123: 19–26. https://doi.org/10.1172/JCI62862.
[47]
Perkins MJ, Van Driest SL, Ellsworth EG, Will ML, Gersh BJ, Ommen SR, et al. Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy. European Heart Journal. 2005; 26: 2457–2462. https://doi.org/10.1093/eurheartj/ehi438.
[48]
Dzau VJ. Cell biology and genetics of angiotensin in cardiovascular disease. Journal of Hypertension. Supplement: Official Journal of the International Society of Hypertension. 1994; 12: S3–S10.
[49]
Kawaguchi H, Kitabatake A. Renin-angiotensin system in failing heart. Journal of Molecular and Cellular Cardiology. 1995; 27: 201–209. https://doi.org/10.1016/s0022-2828(08)80019-3.
[50]
Malik FS, Lavie CJ, Mehra MR, Milani RV, Re RN. Renin-angiotensin system: genes to bedside. American Heart Journal. 1997; 134: 514–526. https://doi.org/10.1016/s0002-8703(97)70089-9.
[51]
Soubrier F, Alhenc-Gelas F, Hubert C, Allegrini J, John M, Tregear G, et al. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proceedings of the National Academy of Sciences of the United States of America. 1988; 85: 9386–9390. https://doi.org/10.1073/pnas.85.24.9386.
[52]
Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Research. 1992; 20: 1433. https://doi.org/10.1093/nar/20.6.1433-a.
[53]
Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circulation Research. 1991; 69: 1185–1195. https://doi.org/10.1161/01.res.69.5.1185.
[54]
Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH. Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation. 1993; 88: 2849–2861. https://doi.org/10.1161/01.cir.88.6.2849.
[55]
Cheng Y, Wang Y, Yin R, Xu Y, Zhang L, Zhang Y, et al. Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy. Frontiers in Endocrinology. 2023; 14: 1162754. https://doi.org/10.3389/fendo.2023.1162754.
[56]
Pilati M, Cicoira M, Zanolla L, Nicoletti I, Muraglia S, Zardini P. The role of angiotensin-converting enzyme polymorphism in congestive heart failure. Congestive Heart Failure (Greenwich, Conn.). 2004; 10: 87–93; quiz 94–95. https://doi.org/10.1111/j.1527-5299.2004.01328.x.
[57]
Chapman D, Weber KT, Eghbali M. Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium. Circulation Research. 1990; 67: 787–794. https://doi.org/10.1161/01.res.67.4.787.
[58]
SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The New England Journal of Medicine. 1991; 325: 293–302. https://doi.org/10.1056/NEJM199108013250501.
[59]
Lamas GA, Pfeffer MA. Left ventricular remodeling after acute myocardial infarction: clinical course and beneficial effects of angiotensin-converting enzyme inhibition. American Heart Journal. 1991; 121: 1194–1202. https://doi.org/10.1016/0002-8703(91)90682-8.
[60]
Renner W, Nauck M, Winkelmann BR, Hoffmann MM, Scharnagl H, Mayer V, et al. Association of angiotensinogen haplotypes with angiotensinogen levels but not with blood pressure or coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study. Journal of Molecular Medicine (Berlin, Germany). 2005; 83: 235–239. https://doi.org/10.1007/s00109-004-0618-0.
[61]
Bloem LJ, Manatunga AK, Tewksbury DA, Pratt JH. The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. The Journal of Clinical Investigation. 1995; 95: 948–953. https://doi.org/10.1172/JCI117803.
[62]
Villard E, Perret C, Gary F, Proust C, Dilanian G, Hengstenberg C, et al. A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy. European Heart Journal. 2011; 32: 1065–1076. https://doi.org/10.1093/eurheartj/ehr105.

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share
Back to top
Rev. Cardiovasc. Med. Print ISSN 1530-6550 Electronic ISSN 2153-8174
Disclaimer
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept