Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to pediatric asthma: A meta-analysis.

OBJECTIVE: The correlation of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism with pediatric asthma risk was assessed in this meta-analysis.
METHODS: PubMed, Web of Science, Embase and CNKI databases were systematically searched for relevant literature, followed by application of odds ratios (OR) along with 95% confidence interval (CI) for determining the strength of relationship.
RESULTS: Seven articles with 802 cases and 632 controls fulfilled the inclusion criteria. As a result, the ACE I/D polymorphism was related to elevated pediatric asthma risk (D vs I: OR = 1.87, 95% CI = 1.59-2.20; dominant model: OR =1.53, 95% CI = 1.28-1.81; recessive model: OR =1.54, 95% CI = 1.28-1.85; DD vs II: OR =2.95, 95% CI = 2.19-3.98; DI vs II: OR = 0.96, 95% CI = 0.78-1.19). Subgroup analysis stratified by race revealed significant interrelation in Asians.
CONCLUSION: This meta-analysis demonstrated that the ACE I/D polymorphism might be related to the risk of pediatric asthma.

Introduction

According to the Global Initiative for Asthma 2019, asthma is a common chronic allergic disorder that involves the respiratory tract and affects an estimated 300 million individuals worldwide. It is a serious global health problem affecting all age groups, with increasing prevalence in many developing countries, rising treatment costs, and a rising burden for patients and professionals. To be specific, asthma is highly heterogeneous and typically includes chronic inflammation of the airway with symptoms including shortness of breath, cough, chest tightness, wheezing and variably reduced expiratory airflow.[2] The complicated pathogenesis of asthma remains largely undefined. However, decreased lung function, allergic disorder, as well as bacterial and viral infections are considered the main risk factors for the persistence and progression of asthma.[3-5] Additionally, variants of more than 40 genes have been reported to have a certain correlation with asthma.[6] Moreover, parental asthma is a potent predictive factor for pediatric asthma, implicating the potent genetic basis of pediatric asthma.[7]

Angiotensin-converting enzyme (ACE), a vital enzyme of the renin-angiotensin system, is mainly expressed in the lung, playing a critical part in asthma pathogenesis.[8] Functionally, ACE is capable of converting angiotensin I to angiotensin II, possibly participating in asthma etiology by interaction with bronchial muscle. ACE can also inactivate various inflammatory peptides, such as substance P and bradykinin, the latter of which is generated in the lungs of patients with asthma.[9] The location of the ACE gene is on the long arm of chromosome 17. In addition, the ACE gene insertion/deletion (I/D) polymorphism is commonly found, with a 287-bp fragment within intron 16. In terms of the correlation with plasma ACE level, homozygous D allele is the highest, sequentially followed by heterozygous one (ID) and homozygous I allele.[10] Previous meta-analysis showed that the ACE I/D polymorphism might enhance Henoch-Schönlein purpura risk.[11]

In the past decade, the correlation of the ACE I/D polymorphism with pediatric asthma vulnerability has been examined in several studies, however, with great controversy. Insufficient power, false-positive outcomes and the mild impacts of the ACE I/D polymorphism on pediatric asthma risk might partially explain the inconsistency. Herein, we determined whether the ACE gene I/D polymorphism was related to pediatric asthma risk in the present meta-analysis.

Materials and methods

Search strategy for identification of studies

PubMed, Embase, Web of Science and CNKI databases were systematically searched for all articles written on the correlation of the ACE I/D polymorphism with pediatric asthma risk (updated to August 2019) using search terms including asthma or asthmatic and polymorphism or mutation or variant and angiotensin-converting enzyme or ACE. Moreover, we manually reviewed the references from the retrieved articles to extract more eligible researches.

Inclusion and exclusion criteria

The abstracts were independently reviewed by two investigators to determine the inclusion or exclusion of the articles, and discrepancies were reached by discussion between the investigators. The inclusion criteria were shown in the following: (a) case-control research concerning pediatric asthma cases and normal controls; (b) research concerning the correlation of the ACE I/D polymorphism with pediatric asthma vulnerability and (c) research with adequate genotype information. The exclusion criteria were shown in the following: (a) not case-control research; (b) duplicates of previous research; (c) studies with inadequate data and (d) meta-analyses, editorials, reviews, letters or case reports.

Data extraction

Two authors extracted data from included articles independently, subsequently reaching consensus on all items. The following data were extracted from each article: last name of first author, race, country, publication date, numbers of genotyped controls and cases, and deviation from Hardy-Weinberg Equilibrium (HWE) of control group.

Statistical analysis

The strength of the relationship of the ACE I/D polymorphism with the susceptibility to pediatric asthma was evaluated by odds ratios (ORs) and their 95% confidence intervals (CIs). Specifically, the following genetic models were used: D vs I, recessive model (II + DI vs DD), dominant model (DD + DI vs II), heterozygote comparison (DI vs II) and homozygote comparison (DD vs II). I[2] test was employed for quantification of the effect of heterogeneity, ranging from 0% to 100% and reflecting the percentage of interstudy variability that was caused by heterogeneity rather than random chance. A value of I[2] > 50% implicated heterogeneity across studies and the subsequent application of a random-effects model. Otherwise, the fixed-effects model was employed. In addition, sensitivity analysis was conducted by removal of a single study and analysis of the remaining data. Finally, publication bias was assessed by Begg funnel plot. STATA version 12.0 (Stata Corporation, College Station, TX, USA) was used for statistical analysis. A p value of less than 0.05 indicated statistical significance.

Results

Study characteristics

In total, 704 potentially relevant researches were retrieved, and seven case-control studies with full-text were finally enrolled in this meta-analysis after eliminating 697 researched according to the inclusion and exclusion criteria.[12-18] The diagram for study selection appears in Figure 1. The control population was mainly collected from healthy populations. The HWE test showed the consistency of genotype distribution with HWE in the controls except for studies by Song et al,[12] Guo and colleagues[15] and Chen et al.[18] Of these, one study focused on Caucasians and six studies focused on Asians. The study features are presented in Table 1.

Figure 1.

Flow diagram for selection of publication.

Table 1.

Characteristics of included studies for meta-analysis.

Study	Year	Area	Race	Cases/Controls	Allele for cases		Allele for controls		Genotypes for cases			Genotypes for controls			HWE test
					D	I	D	I	DD	ID	II	DD	ID	II
Qin[14]	2000	China	Asian	52/40	46	58	24	56	18	10	24	5	14	21	0.29
Song[12]	2001	China	Asian	108/56	127	89	47	65	41	22	45	9	18	29	0.04
Lue[13]	2006	China	Asian	106/102	24	82	20	82	6	48	52	4	42	56	0.25
Guo[15]	2009	China	Asian	149/165	178	120	122	208	71	36	42	41	40	84	0.00
Zheng[17]	2012	China	Asian	198/110	190	206	81	139	75	40	83	15	51	44	0.97
Chen[18]	2012	China	Asian	87/58	95	79	36	80	38	19	30	9	18	31	0.03
Bora[16]	2013	Turkey	Caucasian	102/101	120	84	104	98	32	56	14	22	60	19	0.05

D: deletion; HWE: Hardy-Weinberg equilibrium; I: insertion.

Overall meta-analysis and further subgroup analysis

The combined data revealed that the ACE I/D polymorphism is related to elevated pediatric asthma risk in various genetic models, as indicated in Figure 2 and Table 2 (D vs I: OR = 1.87, 95% CI = 1.59–2.20; recessive model: OR = 1.54, 95% CI = 1.28–1.85; the dominant model: OR = 1.53, 95% CI = 1.28–1.81; DD vs II: OR = 2.95, 95% CI = 2.19–3.98; DI vs II: OR = 0.96, 95% CI = 0.78–1.19). Subgroup analysis by race showed a significant correlation in Asians (Figure 3), and subgroup analysis by HWE revealed a significant relationship in research consistent with HWE. Afterward, sensitivity analysis was conducted by evaluating the impact of each individual paper on the pooled OR via the deletion of one study each time, which revealed no single article affecting the pooled ORs, suggesting the stability of the outcomes (Figure 4).

Figure 2.

Forest plot of odds ratio (OR) for association between angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and pediatric asthma under D vs I. ID: identification.

Table 2.

Summary odds ratios and 95% CI of angiotensin-converting enzyme insertion/deletion polymorphism with pediatric asthma risk.

Variable	N [a]	D vs I	DD vs II	DI vs II	Dominant model	Recessive model
		OR (95% CI) Begg model	OR (95% CI) Begg model	OR (95%CI) Begg model	OR (95% CI) Begg model	OR (95% CI) Begg model
Total	7	1.87 (1.59–2.20) F 1.00	2.95 (2.19–3.98) F 1.00	0.96 (0.78–1.19) F 1.00	1.53 (1.28–1.81) F 1.00	1.54 (1.28–1.85) F 1.00
Ethnicity
Asian	6	2.00 (1.68–2.38) F 1.00	3.11 (2.26–4.28) F 1.00	0.94 (0.65–1.35) R 1.00	1.61 (1.33–1.94) F 1.00	1.64 (1.33–2.01) F 1.00
Caucasian	1	–	–	–	–	–
HWE
Yes	4	1.49 (1.19–1.86) F 1.00	2.39 (1.52–3.75) F 1.00	0.84 (0.56–1.26) R 1.00	1.21 (0.96–1.52) F 1.00	1.30 (1.02–1.65) F 1.00
No	3	2.41 (1.91–3.04) F 1.00	3.50 (2.34–5.25) F 1.00	1.23 (0.86–1.75) F 1.00	2.10 (1.61–2.74) F 1.00	1.98 (1.48–2.64) F 1.00

CI: confidence interval; D: deletion; F: fixed; HWE: Hardy-Weinberg equilibrium; I: insertion; OR: odds ratio; R: random.

Number of comparisons.

Figure 3.

Forest plot of odds ratio (OR) for association between angiotensin-converting enzyme insertion/deletion (I/D)polymorphism and pediatric asthma in Asians under D vs I. ID: identification.

Figure 4.

Sensitivity analysis of odds ratio (OR) for association between angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and pediatric asthma.

Publication bias

The publication bias was assessed by Begg funnel plot (Figures 5 and 6). The shape of the funnel plot suggests no publication bias (all p > .05).

Figure 5.

Begg funnel plot for association between angiotensin-converting enzyme insertion/deletion polymorphism and pediatric asthma.

Figure 6.

Begg funnel plot for association between angiotensin-converting enzyme insertion/deletion polymorphism and pediatric asthma in Asians.

Discussion

Asthma is the most prevalent chronic pediatric disorder, with extremely complicated and largely undefined pathogenesis of asthma, despite several studies reporting various genetic loci and diverse environmental factors as important asthma determinants.[19] The correlation of the ACE I/D polymorphism with pediatric asthma risk has been studied in several research studies, however, with controversial outcomes. This meta-analysis was designed to enhance sample size as well as statistical power by combining similar research for more authentic outcomes. Compared with the previous meta-analysis,[20,21] the present study aimed at pediatric disorder specifically and conducted subgroup analysis.

In this meta-analysis, seven case-control research studies were included. As a result, the ACE I/D polymorphism was related to pediatric asthma vulnerability. Nevertheless, subgroup analyses were further performed because of the potential impact of other confounding factors. To be specific, subgroup analysis by race revealed a significant relationship of pediatric asthma in Asians. Moreover, subgroup analysis stratified by HWE detected a significant correlation in studies consistent with HWE, indicating the authenticity of this meta-analysis. Additionally, sensitivity analysis along with publication bias validated the robustness of our findings.

The mechanism by which the ACE I/D polymorphism affects pediatric asthma risk is currently unclear.[22,23] Typically, ACE plays a critical role in converting the renin-angiotensin system and angiotensin II, thereby increasing the content of vascular smooth muscle cells, affecting aggregation and adhesion of platelets and monocytes, and smooth muscle cell proliferation. In addition, the location of the ACE I/D polymorphism is in an ACE gene intron, accounting for about one-half of ACE plasma-level difference.[10] Taken together, our results suggesting that the ACE I/D polymorphism may be a risk factor for developing asthma are biologically plausible.

Several limitations of this meta-analysis should be addressed. First, seven included studies were conducted mainly in Asian individuals, whereas only one study was conducted in Caucasians, all of which focused on the association of the ACE I/D polymorphism with pediatric asthma, limiting the statistical power. Thus, large-scale research with representative population is required to validate the present findings. Second, all the included studies are retrospective, possibly causing participant selection bias and subsequently influencing the reliability of final outcomes. Third, this meta-analysis enrolled only published literature, without any relevant unpublished ones, which might cause a potential publication bias.

In summary, we demonstrate that the ACE I/D polymorphism might have a correlation with pediatric asthma risk. In addition, large-scale case-control investigations are necessary to determine the potential gene-gene and gene-environment interaction on pediatric asthma risk.