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Abstract

Background:

Some studies have assessed the association between angiotensin-converting enzyme (ACE) I/D polymorphism and acute respiratory distress syndrome (ARDS) risk. However, the results have been inconclusive and contradictory. Therefore, we performed a meta-analysis to investigate the association between ACE I/D polymorphism and ARDS risk.

Methods:

All relevant studies were searched using PubMed and EMBASE. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models or fixed-effects models.

Results:

A total of 14 studies with 5218 subjects were included in this meta-analysis. We found that ACE I/D polymorphism significantly associated with an increased ARDS risk (OR=1.57; 95% CI 1.30–1.89; P<0.00001). In the subgroup analysis by race, Caucasians with ACE I/D polymorphism showed increased ARDS risk (OR=1.63; 95% CI 1.32–2.02; P<0.00001). However, Asians with this polymorphism did not show significantly increased ARDS risk (OR=1.31; 95% CI 0.90–1.90; P=0.95). In the subgroup analysis by age group, adults showed increased ARDS risk (OR=1.60; 95% CI 1.32–1.93; P<0.00001), while pediatric patients did not have increased ARDS risk (OR=1.15; 95% CI 0.57–2.30; P=0.70).

Conclusions:

This meta-analysis suggested that ACE I/D polymorphism might contribute to the susceptibility for ARDS.

Keywords

Angiotensin-converting enzyme polymorphism acute respiratory distress syndrome association study genetics

Introduction

The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. ARDS continues to be both prevalent and very morbid, with an estimated age-adjusted incidence of 86.2 per 100,000 patient years, and reported in-hospital mortality of nearly 40%.¹ Many risk factors for ARDS have been reported. For example, infection, alcohol abuse, cigarette smoke exposure and race have been reported to be associated with ARDS development.² Besides, genetic susceptibility may also be an important determinant of the incidence of ARDS.³

Angiotensin-converting enzyme (ACE) is a key enzyme that converts angiotensin to angiotensin II. Casey et al. found that patients with ARDS and sepsis had markedly decreased serum ACE levels.⁴ Fourrier et al. also suggested that serum ACE levels decreased and were closely correlated with the severity of lung injury.⁵ However, Idell and coworkers found that broncho-alveolar lavage ACE was elevated in some ARDS patients, especially those with infectious causes of lung injury.⁶ Recently, a study indicated that the administration of captopril prevented rats from OA-induced severe lungs injury, with a significantly lower lung injury score, less albumin content and infiltrated cells in the alveoli, decreased wet/dry weight ratio of the lung tissues and improved lung function (PaO2 per fraction of inspired oxygen).⁷

The ACE gene is located on chromosome 17q35 and consists of 26 exons spread over approximately 24 kb. The intron 16 of the ACE gene contains a restriction fragment length polymorphism consisting of the presence (insertion, I) or absence (deletion, D) of a 287-bp alu repeat sequence.⁸ Several previous studies have studied the association between ACE I/D polymorphism and ARDS risk.^9–18 Two meta-analyses regarding this association have been reported.^19,20 Hu et al. suggested that ACE I/D polymorphism may be associated with ARDS among Caucasians.¹⁹ However, Matsuda and colleagues indicated that ACE I/D polymorphism was not associated with susceptibility to ARDS in Caucasians.²⁰ Therefore, the results were inconclusive and contradictory. Moreover, new studies have been reported since then.^17,18 We thus performed a meta-analysis to investigate the association between ACE I/D polymorphism and ARDS risk.

Methods

Publication search

All relevant studies were searched using PubMed and EMBASE. (The last retrieval date was 10 October 2014, using the search terms: ‘acute respiratory distress syndrome or ARDS or ALI or acute lung injury’ and ‘angiotensin-converting enzyme or ACE’.) All found studies were retrieved and only published studies with full-text articles were included. When there was more than publication with duplicate samples, only the newest study was used in this research.

Study selection

The inclusion criteria were as follows: (1) the research was a case-control study or a cohort study; (2) the study investigated the association between ACE I/D polymorphism and ARDS risk; (3) the ACE I/D genotypes of individual groups were provided. The exclusion criteria were as follows: (1) no usable data reported; (2) animal studies; (3) reviews or abstracts.

Data extraction

Two authors extracted the data independently. These data included: the first author, year, country, ethnicity, age group, gender and sample size. Authors were contacted by Email if further study details were needed. Any disagreement was resolved by consensus.

Statistical analysis

Statistical analysis was conducted using Stata software 11.0 (StataCorp, College Station, Texas, USA). A Hardy–Weinberg equilibrium (HWE) test in a healthy control group was conducted using χ² test. Odds ratio (OR) with a 95% confidence interval (CI) was presented for dichotomous data, and significant level was 0.05. The Q-statistic and the I²-statistic were used to measure statistical heterogeneity, and the significant level was 0.10. Effect model selection was on the basis of a heterogeneity test. A fixed-effects model was selected when there was no significant heterogeneity, otherwise a random-effects mode was usedl. Subgroup analyses based on race and age were performed. Cumulative meta-analysis and sensitivity analysis were also conducted. To explore the source of the heterogeneity, Galbraith plots were used. Publication bias was test using Begg’s test and a funnel plot (significant level was 0.05).

Results

Eligible studies

The characteristics of the included studies were listed in Table 1. Ten studies with 5218 subjects were included in this meta-analysis.^9–18 Three studies reported two or three cohorts, thus 14 case-control studies were treated as independent studies. Five studies were conducted with Asian patients and nine studies were performed with Caucasian patients. Two studies used pediatric patients and the rest of the studies used adults. The results of HWE were also shown in Table 1.

Table 1.

Characteristics of the included studies.

First author	Year	Country	Ethnicity	Age group	Gender	Total number (n)	Hardy–Weinberg equilibrium
Marshall 1	2002	UK	Caucasian	Adult	Mixed	2002	Yes
Marshall 2	2002	UK	Caucasian	Adult	Mixed	184	Yes
Marshall 3	2002	UK	Caucasian	Adult	Mixed	270	Yes
Chan	2005	China	Asian	Adult	Mixed	140	Yes
Jerng 1	2006	China	Asian	Adult	Mixed	239	Yes
Jerng 2	2006	China	Asian	Adult	Mixed	311	Yes
Adamzik	2007	Germany	Caucasian	Adult	Mixed	284	Yes
Plunkett	2008	UK	Caucasian	Children	Mixed	212	Yes
Villar	2008	Spain	Caucasian	Adult	Mixed	212	Yes
Lu 1	2011	China	Asian	Adult	Mixed	509	Yes
Lu 2	2011	China	Asian	Adult	Mixed	337	Yes
Cruces	2012	Chile	Caucasian	Children	Mixed	120	Yes
Cardinal-Fernandez	2013	Spain	Caucasian	Adult	Mixed	149	Yes
Tsantes	2013	Greece	Caucasian	Adult	Mixed	249	Yes

Quantitative data synthesis

Previous studies showed that the ACE DD genotype was associated with higher ACE production that ACE ID or II genotype.²¹ Therefore, we investigated the association between ACE I/D polymorphism and ARDS risk in the recessive model (DD vs DI+II). We found that ACE I/D polymorphism significantly associated with an increased ARDS risk (OR=1.57; 95% CI 1.30–1.89; P<0.00001; Figure 1). In the subgroup analysis by race, Caucasians with ACE I/D polymorphism showed increased ARDS risk (OR=1.63; 95% CI 1.32–2.02; P<0.00001). However, Asians with this polymorphism did not show significantly increased ARDS risk (OR=1.31; 95% CI 0.90–1.90; P=0.95). In the subgroup analysis by age group, adults showed increased ARDS risk (OR=1.60; 95% CI 1.32–1.93; P<0.00001), while pediatric patients did not have increased ARDS risk (OR=1.15; 95% CI 0.57–2.30; P=0.70). The main results and subgroup analyses were listed in Table 2.

Figure 1.

Meta-analysis of the association between ACE I/D polymorphism and ARDS risk.

Table 2.

Results of meta-analysis and subgroup analyses.

	Test of association			Model	Heterogeneity
	OR (95% CI)	Z	P Value	Model	χ ²	P Value	I² (%)
Overall	1.57 (1.30–1.89)	4.76	<0.00001	R	45.88	<0.0001	72
Race
Asian	1.31 (0.90–1.90)	1.39	0.16	F	0.69	0.95	0
Caucasian	1.63 (1.32–2.02)	4.47	<0.00001	R	43.28	<0.00001	82
Age group
Adult	1.60 (1.32–1.93)	4.85	<0.00001	R	42.76	<0.0001	72
Children	1.15 (0.57–2.30)	0.38	0.70	F	1.90	0.17	47

R: random-effects model; F: fixed-effects model.

Cumulative meta-analysis was conducted by the assortment of studies by publication time (Figure 2). To determine the stableness of the result, we performed the sensitivity analysis by omitting one study at a time. We found that single study did not impact the pooled OR, indicating that the results of our research were statistically robust (Figure 3).

Figure 2.

Cumulative meta-analysis of associations between ACE I/D polymorphism and ARDS risk.

Figure 3.

Sensitivity analysis of associations between ACE I/D polymorphism and ARDS risk.

There was significant heterogeneity (I²=72%, P<0.0001) in the recessive genetic model. The Galbraith plot was used to find the source of the heterogeneity. As shown in Figure 4, three studies were outliers. After excluding these studies, the between-study heterogeneity effectively decreased and there was no obvious heterogeneity among the 11 remaining studies (I²=0%, P=0.69). Besides, the result was marginally significant (OR=1.27, 95% CI 1.00–1.61, P=0.05).

Figure 4.

Galbraith plot of associations between ACE I/D polymorphism and ARDS risk.

Egger’s test and Begg’s funnel plot were conducted to assess the publication bias. The shape of funnel plot was symmetry (Figure 5). Egger’s test did not detect obvious publication bias (P=0.913).

Figure 5.

Begg’s funnel plot for associations between ACE I/D polymorphism and ARDS risk.

Discussion

This meta-analysis of 14 case-control studies evaluated the association between ACE I/D polymorphism and ARDS risk. We found that ACE I/D polymorphism might be a risk factor for developing ARDS. This result suggested that ACE DD genotype carriers might have increased ARDS risk compared to ID or II carriers. In the race subgroup analysis, Caucasians but not Asians with ACE I/D polymorphism showed increased ARDS risk. There were only three studies with Asians. More studies with Asian populations are still needed to validate our results. In addition, we also found that ACE I/D polymorphism was associated with ARDS risk in adults. Since there were only two studies with pediatric patients, more studies with these populations are needed to validate the result of this meta-analysis. To the best of our knowledge, this was the most comprehensive meta-analysis of the association between ACE I/D polymorphism and ARDS risk.

Rigat et al. found that plasma ACE levels of subjects who carried the DD genotype were twofold compared to levels found in patients carrying the II genetic polymorphism (ID subjects having intermediate levels).²² Previous studies suggested that the activation of the renin–angiotensin system in the lung may be related to the development of ARDS, probably because of decreased alveolar epithelial cell survival,⁵ changes in vascular permeability²³ or fibroblast proliferation.²⁴ ACE levels were elevated in BAL and administration of ACEI protected the rats from severe lungs injury.^6,7 Thus, ACE I/D polymorphism might be associated with increased ARDS risk.

This meta-analysis had several limitations. Firstly, the sample size for this polymorphism was relatively small. Thus, the statistical power of genetic effects identified might be hampered. However, results from cumulative meta-analysis and sensitivity analysis suggested that our results are reliable and robust. Secondly, the number of included studies was moderate. Thus, the results of this meta-analysis might be influenced by the factors like publication bias, etc. However, no publication bias was found in our study. Third, our study did not address gene–gene and gene–environment interactions.

Conclusion

In conclusion, this meta-analysis indicated that ACE I/D polymorphism may be associated with the risk of ARDS. Well-designed studies with larger sample size and more ethnic groups should be considered to further confirm this association.

Footnotes

Conflict of interest

None declared.

Funding

This research was supported by the program for Development of Key Disciplines of Shanghai (No. ZK2012A23).

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