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Journal of the Renin-Angiotensin-Aldosterone System: JRAAS logoLink to Journal of the Renin-Angiotensin-Aldosterone System: JRAAS
. 2021 Mar 16;22(1):1470320321995074. doi: 10.1177/1470320321995074

Association between angiotensin converting enzyme gene polymorphism and essential hypertension: A systematic review and meta-analysis

Mingyu Liu 1,✉, Jian Yi 2, Wenwen Tang 3
PMCID: PMC7983243  PMID: 33726555

Abstract

Background:

The current meta-analytic study explored the relation between ACE gene insertion/deletion (I/D), and the risk of EH by reviewing relevant trials so as to determine the association between Angiotensin Converting Enzyme (ACE) gene polymorphism and essential hypertension (EH) susceptibility.

Methods:

Relevant studies published before May 2019 were collected from the PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP databases.

Results:

Fifty-seven studies involving a total of 32,862 patients were included. These studies found that ACE gene D allele was associated with higher EH susceptibility in allelic model, homozygote model, dominant model, and regressive model, and that Asian population with ACE gene D allele showed a higher EH susceptibility in all these models. Moreover, ACE gene D allele was found closely related to a higher EH susceptibility in the subgroups of HWE, NO HWE, Caucasian population, and Mixed population, with the majority being males in allelic model, homozygote model, and regressive model and the majority being females in allelic model.

Conclusion:

ACE gene D allele is associated with an overall higher EH susceptibility, which is confirmed in the subgroup analysis of Asian population, HWE, NO HWE, Caucasian population, and Mixed population.

Keywords: Angiotensin converting enzyme, gene polymorphism, essential hypertension, meta-analysis

Introduction

Essential hypertension (EH), abbreviated as hypertension, is a common and frequently-occurring disease mainly manifested by elevated blood pressure, and it remains one of the principal causes of death in cardiovascular diseases. With the acceleration of population aging and the growing number of obese people, the prevalence rate of EH shows an increasing trend in both developed and developing countries. Hypertension is a disease prominently featured by family clustering. The incidence rate of hypertension in children whose parents both suffer from the health problem can be as high as 46%, and about 60% of hypertensive patients can be asked about family history.1–3

Key gene dominant inheritance and polygene associated inheritance are the two main modes of inheritance of hypertension. In the genetic phenotype of hypertension, occurrence, height, and other factors related to blood pressure complications, such as obesity, are also hereditary, and the incidence of elevated blood pressure can be hereditary. Candidate genes for hypertension include renin–angiotensin system (RAS) genes, sodium system related genes, signal transduction pathway related genes, and endothelin system genes. Angiotensin converting enzyme (ACE) is an important enzyme in the RAS system. The relationship between this gene polymorphism and the genetic heterogeneity of hypertension has been extensively researched by scholars around the world.4,5

The relation between ACE gene polymorphism and essential hypertension research is currently a research hot spot, and most research results include ACE gene polymorphism and the pathogenesis of EH. Besides, there is a certain relationship between the risk factors of cardiovascular diseases. Therefore, whether the ACE gene I/D polymorphism can be employed as a clinical and subclinical marker for the prognosis observation, diagnosis, and treatment of essential hypertension still needs further research. This meta-analysis was performed with all available literature to obtain updated evidence about the association between ACE gene insertion/deletion (I/D) and EH susceptibility.

Materials and methods

Searching strategy

To identify studies on the association between ACE gene insertion/deletion (I/D) and the risk of EH, relevant studies published before May 2019 were retrieved from the Cochrane, Pubmed, Embase, CNKI, VANFUN, and VIP databases. The references of all the identified articles were also retrieved to identify additional related studies. The search terms were as follows: polymorphism, variant, genotype, gene, angiotensin converting enzyme, ACE, hypertension, essential hypertension, and EH. These terms were searched in combination with “AND” or “OR.” The literature review was performed independently by two investigators, with a third resolving any disputes as needed.

Following the PICOS (Participants, Interventions, Comparisons, Outcomes, and Study Design) principle, the key search terms included (P) patients with EH; (I) detection of ACE gene polymorphism; (C/O) comparison of ACE gene polymorphism between the EH group and the control group; (S) case-control trial or cohort study.

Study selection criteria

Included studies met the following criteria: (1) case-control studies or cohort studies; (2) the subjects in the case group were patients with EH; (3) the subjects in the control group were healthy controls or patients without EH; (4) the research factors were ACE gene insertion/deletion (I/D); and (4) articles were written in English or Chinese.

Studies were excluded for meeting the following criteria: (1) repeated articles or results; (2) clear data errors; (3) case reports, case-control studies, theoretical research, conference reports, systematic reviews, meta-analyses, or other forms of research or comment that were not designed in a randomized controlled manner; (4) irrelevant outcomes; and (5) lack of a comparable control group.

Two investigators independently determined whether studies met the inclusion criteria, with a third resolving any disputes as needed.

Data extraction and quality assessment

Two categories of information were extracted from each included study: basic information and primary study outcomes. Basic information relevant to this meta-analysis was as follows: author names, year of publication, country, ethnicity, sample size, age, polymorphism, and genotyping method. Primary clinical outcomes relevant to this analysis were genotype frequencies (ACE gene insertion/deletion (I/D)) in the EH group and control groups. The data extraction was performed independently by two investigators, with a third resolving any disputes as needed.

Statistical analysis

STATA v12.0 (TX, USA) was used for all statistical analyses. Heterogeneity in the study results was assessed using chi-squared and I2 tests, and appropriate analysis models (fixed-effect or random-effect) were determined. A chi-squared p ⩽ 0.05 and an I2 > 50% indicated high heterogeneity, and thus a random-effects model was used. A chi-squared p > 0.05 and an I2 ⩽ 50% indicated acceptable heterogeneity, and thus a fixed-effects model was used instead. Egger’s test and Begg’s test were performed to determine publication bias. On condition that the Hady Weinberg equilibrium (HWE) genetic balance test was neither provided in the original text nor performed in the control group, Stata v12.0 was used to obtain corresponding results (p value). Five commonly used gene models were selected for this meta-analysis: allelic model (D vs I), homozygote model (DD vs II), heterozygote model (DI vs II), dominant model (DD + DI vs II), and regressive model (DD vs DI + II). All the indexes and statistics were analyzed by OR and 95%CI.

Overview of included studies

A total of 877 articles were screened in the initial key word search, of which 786 were excluded after title/abstract review. The remaining 91 articles were subject to a complete full-text assessment, and as a result, 34 articles were excluded due to the following reasons: (1) theoretical research (11); (2) without clinical outcomes (18); (3) repeated articles (2); and (4) lack of a control group (3). We ultimately identified 57 studies6–62 that met the inclusion criteria of the current meta-analysis, which incorporated a total of 16,298 EH patients in the EH group and 16,564 healthy controls or patients without EH in the control group. Study selection is outlined in Figure 1. Table 1 summarizes the basic information of each study, including author names, year of publication, country, ethnicity, sample size, age, polymorphism, and genotyping method.

Figure 1.

Figure 1.

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Literature search and selection strategy.

Table 1.

The basic characteristics description of included studies.

Study Country Ethnicity No. of patients Age Genotype of EH group Genotype of control group
EH group Control group EH group Control group II ID DD II ID DD
Yi et al. 8 China Asian 198 131 50 42 67 95 36 34 69 28
Yi et al. 8 China Asian 120 102 53 41 22 74 24 26 50 26
Fan et al. 9 China Asian 921 951 — — 311 427 183 333 454 164
Fan et al. 9 China Asian 285 312 — — 113 126 46 113 156 40
Wang Xiaoyun 10 China Asian 81 30 65.85 65.23 38 9 34 18 7 5
Yuan Fengxian 11 China Asian 69 99 50.7 — 15 30 24 39 45 14
Xu Xiangjun 18 China Asian 28 29 64.43 61.48 12 11 5 10 13 6
Tian Lihong 19 China Asian 56 40 66.8 64.9 12 20 24 11 21 8
Dong-Ming et al. 12 China Asian 146 108 — — 58 57 31 50 40 18
Lifang 20 China Asian 158 314 46.7 35.1 60 69 28 130 153 54
Shi Zhilin 21 China Asian 128 150 — — 47 67 14 62 78 10
Lv Dongxia 22 China Asian 102 107 — — 44 42 16 42 46 19
Liu et al. 23 China Asian 100 100 59.4 54.4 13 43 44 21 50 29
Zhang et al. 24 China Asian 115 96 — — 24 51 40 33 45 18
He Fengrong 25 China Asian 209 303 49 48.4 77 111 21 124 134 45
He Fengrong 25 China Asian 189 303 48.7 48.4 78 87 24 124 134 45
Yun Meiling 26 China Asian 106 97 65.84 74.78 59 30 17 39 43 15
Liang Riming 27 China Asian 64 122 62.07 61.08 30 18 16 56 50 16
Song Xin et al. 7 China Asian 91 109 56.07 50.36 28 43 20 54 41 14
Jiang et al. 13 China Asian 220 235 62.2 61.1 83 108 29 110 112 13
Qi Xiaohua 29 China Asian 100 100 — — 39 41 20 32 54 14
Zhao Yan 30 China Asian 200 185 58.2 51.9 62 114 24 89 86 10
Niu et al. 14 China Asian 1089 926 50.62 52.99 335 501 253 300 451 175
Zhou Biao 31 China Asian 112 103 — — 31 36 45 38 44 21
Gao Bingfeng 32 China Asian 78 62 — — 21 43 14 25 33 4
Dong et al. 33 China Asian 120 30 63.64 60.3 51 43 26 94 13 3
Gong Hongtao 34 China Asian 200 192 53.7 51.6 58 46 56 74 94 24
Yao Bingju 15 China Asian 125 1100 — — 42 50 33 34 48 28
Lin Huizhong 35 China Asian 1380 888 60.6 59.7 534 621 225 346 421 121
Xue et al. 36 China Asian 110 43 — — 28 44 38 19 19 5
Lai Yanxian 37 China Asian 108 102 — — 27 50 27 42 47 13
Fan et al. 16 China Asian 3630 826 — — 1286 1689 626 268 392 158
Jhawat 17 India Asian 510 279 — — 154 250 106 60 140 70
Bin 6 China Asian 486 457 62.65 62.67 167 181 138 159 227 71
Liu Longmei et al. 28 China Asian 50 50 52.1 52.1 13 16 21 20 18 12
Krishnan et al. 38 India Mixed 280 220 43.6 42.7 59 68 81 118 58 44
Amrani et al. 39 Algeria Caucasian 75 70 48.1 43.1 25 40 10 43 25 2
Abbas S et al. 40 India Mixed 138 116 41.29 40.03 37 83 18 12 70 34
Heidari F et al. 41 Malaysia Asian 72 72 47.22 46.92 4 25 43 18 35 19
Rasyid et al. 42 Indonesia Asian 104 99 — — 21 34 49 21 34 44
Srivastava et al. 43 India Mixed 222 252 51.6 49.7 42 106 74 16 98 138
Gupta et al. 44 India Mixed 106 110 53.9 51.96 27 49 30 33 50 27
Das et al. 45 India Mixed 35 35 — — 12 4 19 14 18 3
Ramachandran et al. 46 Malaysia Asian 65 70 58.48 46.2 24 34 7 40 28 2
Dell’omo et al. 47 Italy Caucasian 79 16 48 47 7 36 36 2 8 6
Zapolska-Downar et al. 48 Poland Caucasian 40 40 24.1 24.7 6 26 8 13 17 10
Fu et al. 49 Japan Asian 275 441 61.7 64.9 117 113 45 195 194 52
Demirel et al. 50 Italy Caucasian 129 129 45 35.6 23 63 43 20 51 58
Stankovic et al. 51 Yugoslavia Caucasian 105 210 — — 31 85 59 34 115 61
Morshed et al. 52 Bangladesh Asian 44 59 47.3 43.5 5 17 22 19 26 14
Gesang et al. 53 China Asian 103 123 49 47 29 47 27 48 60 15
Fu Y et al. 54 China Asian 235 510 60.9 64.7 5 68 162 20 158 332
Higaki et al. 55 Japan Asian 1200 3814 65.9 57.7 525 529 191 1638 1708 468
Bedir et al. 56 Turkey Caucasian 165 143 49.8 58.9 23 77 65 19 82 42
Sugiyama et al. 57 Japan Asian 711 532 63.8 55.3 290 322 99 200 247 85
Mondorf et al. 58 Germany Caucasian 121 125 46.42 47.3 31 55 35 19 66 40
Maeda et al. 59 Japan Asian 41 34 59.3 61.1 13 14 14 16 9 9
Vassilikioti et al. 60 Greece Caucasian 98 84 — — 23 45 30 15 40 29
Maguchi et al. 61 Japan Asian 84 84 48 48 40 29 15 28 39 17
Ishigami et al. 62 Japan Asian 87 95 59.3 57.4 44 26 17 35 43 17
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Meta-analysis of ACE gene insertion/deletion (I/D) polymorphism and EH susceptibility

All the included studies reported the association between ACE gene insertion/deletion (I/D) polymorphism and EH susceptibility. In view of the significant heterogeneity between studies (chi-squared p < 0.05 and I2 > 50%), a random-effects model was established to analyze the five gene models in all the subgroup analyses except for allelic model in the subgroup of Caucasian (D vs I) (chi-squared p > 0.05 and I2 < 50%).

The results suggested that ACE gene D allele was associated with a higher EH susceptibility as compared with ACE gene I allele, as evidenced by the following statistics: allelic model (D vs I) (OR: 2.273, 95%CI: 2.068–2.499); homozygote model (DD vs II) (OR: 1.472, 95%CI: 1.247–1.739); dominant model (DD + DI vs II) (OR: 1.178, 95%CI: 1.053–1.319); and regressive model (DD vs DI + II) (OR: 1.422, 95%CI: 1.240–1.630).

The subgroup analysis also indicated that the Asian population with ACE gene D allele was associated with a higher EH susceptibility as compared with those with ACE gene I allele, as demonstrated by the following data: allelic model (D vs I) (OR: 2.199, 95%CI: 1.991–2.430); homozygote model (DD vs II) (OR: 1.545, 95%CI: 1.314–1.817); dominant model (DD + DI vs II) (OR: 1.189, 95%CI: 1.066–1.326); regressive model (DD vs DI + II) (OR: 1.488, 95%CI: 1.298–1.706). Moreover, ACE gene D allele was associated with a higher EH susceptibility in the subgroup of HWE, as evidenced by the statistics below: allelic model (D vs I) (OR: 2.158, 95%CI: 1.976–2.356); homozygote model (DD vs II) (OR: 1.394, 95%CI: 1.182–1.644); regressive model (DD vs DI + II) (OR: 1.372, 95%CI: 1.193–1.578). ACE gene D allele was associated with a higher EH susceptibility in the subgroup of NO HWE, as shown by the following results: allelic model (D vs I) (OR: 3.158, 95%CI: 1.948–5.121); regressive model (DD vs DI + II) (OR: 1.782, 95%CI: 1.070–2.967). The Caucasian population with ACE gene D allele were associated with a higher EH susceptibility, as demonstrated by the following statistics: allelic model (D vs I) (OR: 2.448, 95%CI: 2.021 2.965). The Mixed population with ACE gene D allele was associated with a higher EH susceptibility, as suggested by the data below: allelic model (D vs I) (OR: 2.516, 95%CI: 1.289–4.911). All these results were shown in Figures 2 and 3 and Table 2.

Figure 2.

Figure 2.

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Forest plot of studies evaluating the relationship between ACE I/D polymorphism and EH risk based on dominant model.

Figure 3.

Figure 3.

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Funnel plot analysis of included studies concerning ACE I/D polymorphism.

Table 2.

Meta-analysis of ACE gene insertion/deletion (I/D) polymorphisms and EH susceptibility.

Gene type Race N (case/control) OR (95%CI) p * I 2 p # p Value
Begg Egger
DD vs II + ID
Overall 16,298/16,564 1.422 (1.240, 1.630) 0 75.30% 0 0.005 0.004
Mixed 781/733 1.274 (0.470, 3.458) 0 93.60% 0.634 0.624 0.477
Caucasian 856/876 1.185 (0.831, 1.689) 0.011 59.70% 0.349 0.297 0.331
Asian 14,661/14,955 1.488 (1.298, 1.706) 0 69.50% 0 0.008 0.001
HWE 15,021/15,507 1.372 (1.193, 1.578) 0 74.00% 0 0.008 0.010
NO HWE 1277/1057 1.782 (1.070, 2.967) 0 79.90% 0.026 0.404 0.578
DD+ID vs II
Overall 16,298/16,564 1.178 (1.053, 1.319) 0 73.20% 0.004 0.021 0.024
Mixed 781/733 0.850 (0.311, 2.322) 0 92.50% 0.752 0.327 0.274
Caucasian 856/876 1.219 (0.773, 1.922) 0.001 68.20% 0.394 0.940 0.205
Asian 14,661/14,955 1.189 (1.066, 1.326) 0 68.20% 0.002 0.004 0.003
HWE 15,021/15,507 1.109 (0.999, 1.231) 0 64.40% 0.053 0.018 0.031
NO HWE 1277/1057 1.527 (0.904, 2.578) 0 86.30% 0.114 0.835 0.638
DD vs II
Overall 16,298/16,564 1.472 (1.247, 1.739) 0 77.20% 0 0.005 0.008
Mixed 781/733 1.010 (0.242, 4.212) 0 94.70% 0.989 1.000 0.750
Caucasian 856/876 1.268 (0.756, 2.127) 0.005 63.90% 0.368 0.211 0.053
Asian 14,661/14,955 1.545 (1.314, 1.817) 0 71.70% 0 0.003 0.001
HWE 15,021/15,507 1.394 (1.182, 1.644) 0 73.90% 0 0.006 0.011
NO HWE 1277/1057 1.920 (0.955, 3.861) 0 85.10% 0.067 0.835 0.813
ID vs II
Overall 16,298/16,564 1.037 (0.935, 1.150) 0 61.60% 0.495 0.170 0.169
Mixed 781/733 0.699 (0.297, 1.644) 0 87.10% 0.411 0.624 0.154
Caucasian 856/876 1.142 (0.744, 1.755) 0.010 60.10% 0.544 0.144 0.217
Asian 14,661/14,955 1.039 (0.939, 1.150) 0 56.00% 0.459 0.083 0.074
HWE 15,021/15,507 0.993 (0.901, 1.094) 0 51.70% 0.881 0.103 0.231
NO HWE 1277/1057 1.272 (0.786, 2.059) 0 80.10% 0.327 0.404 0.669
D vs I
Overall 16,298/16,564 2.273 (2.068, 2.499) 0 80.40% 0 0 0
Mixed 781/733 2.516 (1.289, 4.911) 0 92.60% 0.007 0.624 0.935
Caucasian 856/876 2.448 (2.021, 2.965) 0.172 30.80% 0 0.095 0.105
Asian 14,661/14,955 2.199 (1.991, 2.430) 0 79.60% 0 0 0
HWE 15,021/15,507 2.158 (1.976, 2.356) 0 74.40% 0 0 0
NO HWE 1277/1057 3.158 (1.948, 5.121) 0 91.00% 0 0.532 0.228
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*

p value of Heterogeneity chi-squared.

#

p value of Pooled statistic.

Meta-analysis of ACE gene insertion/deletion (I/D) polymorphism and EH susceptibility in males

Eight studies9,11,16,23,52,53,55,57 involving a total of 7124 EH patients in the EH group and 6967 healthy controls or patients without EH in the control group reported the association between ACE gene insertion/deletion (I/D) polymorphism and EH susceptibility in males. Studies that were significantly heterogeneous (chi-squared p < 0.05 and I2 > 50%) were analyzed using a random-effects model, while the rest studies were analyzed using a fixed-effects model (chi-squared p > 0.05 and I2 < 50%).

The results demonstrated that ACE gene D allele was associated with a higher EH susceptibility in males, as evidenced by the following statistics: allelic model (D vs I) (OR: 1.834, 95%CI: 1.688–1.993); homozygote model (DD vs II) (OR: 1.260, 95%CI: 1.076–1.477); regressive model (DD vs DI + II) (OR: 1.286, 95%CI: 1.117–1.480). All these results were presented in Figure 4 and Table 3.

Figure 4.

Figure 4.

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Forest plot of studies evaluating the relationship between ACE I/D polymorphism and EH risk in males based on dominant model.

Table 3.

Meta-analysis of ACE gene insertion/deletion (I/D) polymorphisms and EH susceptibility in male.

Gene type N (case/control) OR (95%CI) p * I 2 p # p Value
Begg Egger
DD vs II + ID
7124/6967 1.286 (1.117, 1.480) 0.062 46.20% 0 0.754 0.451
DD+ID vs II
7124/6967 1.254 (0.966, 1.628) 0.185 29.20% 0.211 0.754 0.995
DD vs II
7124/6967 1.260 (1.076, 1.4766) 0.036 51.60% 0.089 0.917 0.7
ID vs II
7124/6967 1.008 (0.896, 1.135) 0.477 0.00% 0.889 1 0.553
D vs I
7124/6967 1.834 (1.688, 1.993) 0.065 45.60% 0 0.348 0.219
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*

p value of Heterogeneity chi-squared.

#

p value of Pooled statistic.

Meta-analysis of ACE gene insertion/deletion (I/D) polymorphism and EH susceptibility in females

Eight studies9,11,16,23,52,53,55,57 involving a total of 7,124 total EH patients in the EH group and 6,967 healthy controls or patients without EH in the control group reported the association between ACE gene insertion/deletion (I/D) polymorphism and EH susceptibility in females. For studies that were significantly heterogeneous (chi-squared P < 0.05 and I2 > 50%), a random-effects model was used to analyze allelic model (D vs I), homozygote model (DD vs II), and regressive model (DD vs DI + II), while for the rest studies (chi-squared P > 0.05 and I2 < 50%), a fixed-effects model was used to analyze the other two models.

The results showed that ACE gene D allele was associated with a higher EH susceptibility in females, as evidenced by the following statistics: allelic model (D vs I) (OR: 1.840, 95%CI: 1.582-2.141).

All these results were presented in Figure 5 and Table 4.

Figure 5.

Figure 5.

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Forest plot of studies evaluating the relationship between ACE I/D polymorphism and EH risk in females based on dominant model.

Table 4.

Meta-analysis of ACE gene insertion/deletion (I/D) polymorphisms and EH susceptibility in female.

Gene type N (case/control) OR (95%CI) p * I 2 p # p Value
Begg Egger
DD vs II + ID
7124/6967 1.206 (0.909, 1.599) 0.004 64.60% 0.194 0.118 0.04
DD + ID vs II
7124/6967 0.974 (0.872, 1.087) 0.133 35.60% 0.634 0.076 0.033
DD vs II
7124/6967 1.264 (0.903, 1.770) 0.002 67.20% 0.173 0.251 0.033
ID vs II
7124/6967 0.953 (0.847, 1.073) 0.749 0.00% 0.427 0.175 0.047
D vs I
7124/6967 1.840 (1.582,2.141) 0.026 54.00% 0 0.016 0.017
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*

p value of Heterogeneity chi-squared.

#

p value of Pooled statistic.

Discussion

It is generally believed that EH is caused by the interaction between multi-gene heredity and environment, while the true cause of the disease remains unclear. As the most common epidemic disease in modern times, EH seriously endangers human health and can further lead to coronary atherosclerosis. EH is acknowledged as one of the major risk factors for death and serious diseases, including heart disease, stroke, heart failure, and kidney failure. EH is closely related to multiple factors, and statistics from studies at home and abroad shows that the influence of genetic factors on blood pressure accounts for 30%–50% of all their effects on the pathogenesis of EH.1–3

The renin-angiotensin system (RAS) has significant functions in blood pressure regulation, electrolyte balance, vascular tension, and cardiovascular remodeling. As a membrane binding enzyme, ACE is located in vascular endothelial cells and widely distributed in the body. ACE is a key enzyme of RAS, and it can catalyze angiotensin I into angiotensin II, a strong vasoconstrictor, and slow down inactive shock peptide vasodilation. Given the role of RAS in blood pressure regulation, the ACE gene may be a candidate gene for treating EH.37–39

The gene-encoding ACE is an important candidate gene for cardiovascular disease, and its 16 intron insertion/deletion (I/D) polymorphism in the non-coding region can cause the presence or absence of a 287 bp DNA fragment. Studies on high-accutase and Japanese populations demonstrated that ACE insertion/deletion polymorphism accounts for 50% of the variation in plasma ACE levels. Ang II is a powerful vasoconstrictor converted from Ang I by ACE, and it affects the structures of the arterial wall and induces arteriosclerosis by promoting cell growth or extracellular matrix synthesis. ACE inactivates bradykinin and leads to the proliferation of vascular smooth muscle cells.4–6

In the present study, we found that ACE gene D allele was associated with a higher EH susceptibility in allelic model, homozygote model, dominant model, and regressive model. The Asian population with ACE gene D allele was related to a higher EH susceptibility in allelic model, homozygote model, dominant model, and regressive model. Moreover, ACE gene D allele was found associated with a higher EH susceptibility in the subgroups of HWE, NO HWE, Caucasian population, and Mixed population. In addition, ACE gene D allele was associated with a higher EH susceptibility in males in allelic model, homozygote model, and regressive model as well as a higher EH susceptibility in females in allelic model.

It should be noted that there were certain limitations in the present analysis, which inevitably precluded more in-depth analyses. First, only articles written in English and Chinese were included. Second, the exclusion/inclusion criteria and the severity of EH differed in various individual studies. Third, environmental factors such as smoking, high-fat diet, antioxidant intake, use of certain lipid-lowering drugs, or hormone varied among the patients. Fourth, only pooled data were analyzed due to the unavailability of individual patient data.

Conclusion

Our results indicate that ACE gene D allele is associated with an overall higher EH susceptibility in Asian population, HWE, NO HWE, Caucasian population, and Mixed population in both males and females.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

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