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Abstract

Background and objective:

Whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene increases susceptibility to allergic rhinitis (AR) is still undetermined. Therefore, this meta-analysis was performed to systematically assess the possible association between them.

Methods:

The OVID, Medline, Embase, Web of Science, CNKI and Wangfang databases were searched to identify the eligible studies focusing on the association between ACE I/D polymorphism and susceptibility to AR.

Results:

A total of 1410 subjects from six studies were subjected to meta-analysis. In the overall analysis, ACE I/D polymorphism had a statistically significant association with increased AR risk under all genetic models (p<0.05). In the subgroup analysis by ethnicity, significant elevated AR risks were associated with ACE I/D polymorphism in Asians under all genetic models (p<0.05) and in Caucasians under under allele contrast, homozygous comparison and recessive models (p<0.05). In the subgroup analysis by age, ACE I/D polymorphism was associated with significant elevated risks of AR in adults (p<0.05) but not in children (p>0.05) under all genetic models.

Conclusions:

The ACE I/D polymorphism may be a risk factor for AR and studies with large sample size and representative population are warranted to verify this finding.

Keywords

Angiotensin-converting enzyme insertion/deletion gene polymorphism meta-analysis allergic rhinitis

Introduction

Allergic rhinitis (AR) is a complex immunoglobulin (Ig) E-mediated atopic disease affecting approximately 10–30% of the general population, especially in industrialized nations.¹ Its main characteristics are defined as sneezing, rhinorrhea, nasal stuffiness and nasal itching and may be involved in an imbalance in the Th1/Th2 immune response.^2,3 Although the exact pathogenetic mechanisms of AR are still unknown, there is ample evidence suggesting that AR is a complex multifactorial disorder including both genetic and environmental factors^4–8 and some low-penetrant genes have been identified as potential AR susceptibility genes.^9–11 Among them, an important one is angiotensin converting enzyme (ACE), which contains 26 exons and 25 introns and is located on chromosome 17q23. ACE is essential in converting angiotensin I into angiotensin II, which is mainly an effector molecule in the renin-angiotensin system (RAS) and acts as pro-inflammatory modulator in the augmentation of immune responses.^12–14

The ACE I/D is a single nucleotide polymorphism (SNP) of ACE. The ACE I/D polymorphism is defined in the light of the presence (insertion, I) or absence (deletion, D) of a 287 bp repeat sequence within intron 16 of the ACE gene.^15,16 ACE I/D polymorphism which plays a critical role in regulating ACE protein expression and is crucial in atopy, may influence the strength of immunological response and has been reported to be associated with atopic disorders, inflammatory diseases and cancers.^17–22

To date, a series of studies have focused on the relation between ACE I/D polymorphism and AR risk.^23–28 Nevertheless, the results were inconclusive and inconsistent. Several papers have reported that a statistically significant correlation was found between ACE I/D SNP and AR risk.^23,26,27 Conversely, the results from other studies suggested that the ACE I/D SNP was not associated with AR risk.^24,25,28 Therefore, we performed this meta-analysis in order to precisely assess the possible association of ACE I/D polymorphism with the susceptibility of developing AR.

Materials and methods

Literature search strategy

The OVID, Medline, Embase, Web of Science, CNKI and Wangfang databases (up to June 2013) were searched to identify studies focusing on the association between ACE I/D polymorphism and susceptibility to AR. The search terms were as follows: “ACE”, ”angiotensin-converting enzyme”, “allergic rhinitis”, “hayfever”, “pollinosis”, “SNP or polymorphism or variant” and the combination of them. The literature retrieval was performed by two authors (H Lin and D Lin) independently. Relevant reviews and abstracts of meetings were searched for related studies. No language restriction was set.

Inclusion and exclusion criteria

Eligible studies which satisfied the following inclusion criteria were be included if: (a) the study clearly assessed the association between ACE I/D polymorphism and AR risk; (b) the diagnosis of allergic rhinitis was clearly described in the study; (c) the normal healthy controls had no diagnosis of atopic diseases such as asthma or AR . On the other hand, the exclusion criteria were: (a) studies without normal healthy controls; (b) studies without essential data and information; (c) reviews, letters, or meeting proceedings.

Data extraction

Two authors (H Lin and D Lin) performed the extraction of relevant data from all of the eligible studies. Disagreement was resolved by discussion between two authors (H Lin and D Lin). The relevant data listed below were extracted: name of first author, publishing year, country, ethnicity, age, total number of AR patients and controls, and distribution of genotypes in these two groups and p-value of Hardy-Weinberg equilibrium tested in controls. The categorization of ethnicity comprised Caucasian and Asian. The categorization of age included adults and children.

Statistical analysis

Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the connection between ACE I/D polymorphism and susceptibility to AR on the basis of the distinct genotype and allele frequencies of ACE I/D in two groups . The five distinct genetic models comprised allele contrast (D v I), homozygous comparison (DD v II), heterozygous comparison (ID v II), dominant model (ID+DD v II) and recessive model (DD v ID+II). We used the I² statistic to check heterogeneity. A p-value of heterogeneity less than 0.1 was confirmed as statistically significant. The summary ORs were calculated under fixed effects model in the case that p-value of heterogeneity was more than 0.1. Otherwise, we used random effects model to perform the data calculation. Hardy-Weinberg equilibrium (HWE) in controls was assessed by the online program (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). Funnel plots, Begg’s test and Egger’s linear regression method were used to evaluate publication bias. It was confirmed that values of p<0.05 were statistically significant to evaluate the data except the heterogeneity test. We conducted subgroup analyses by ethnicity and age stratification. In addition, sensitivity analysis was conducted to verify the impact of individual study respectively and to exclude the studies that significantly deviated from the HWE. All the data statistics and analyses were conducted by using Stata version 12.0 (Stata Corporation, College Station, Texas, USA).

Results

Study characteristics

The election process is summarized by the flow diagram in Figure 1. In summary, a total of 51 potentially relevant papers were identified after searching the OVID, Medline, Embase, Web of Science, CNKI and Wangfang databases. Two authors (H Lin and D Lin) excluded ineligible articles independently. Thirty-three papers including duplicates or unrelated articles were excluded during screening. Then, 18 potentially relevant papers on ACE I/D polymorphism and susceptibility to AR were selected. After careful examination of these papers, 12 papers were excluded for the following reasons: two were reviews, 10 reported for other purposes. As a result, six eligible studies with a total sample size of 741 AR patients and 669 controls were included. One study was performed in Caucasians, and five studies were conducted in Asian populations. Two studies involved children and four recruited adults. Therefore, we performed subgroup analysis by ethnicity and age stratification. Details of the subjects in these studies are outlined in Table 1.

Figure 1.

The flow diagram of included/excluded studies. ACE: angiotensin-converting enzyme; I/D: insertion/deletion.

Table 1.

Characteristics of included studies.

Authors	Year	Country	Ethnicity	Age	Total number		Cases					Controls					HWE of controls
					Cases	Controls	II	ID	DD	I	D	II	ID	DD	I	D	HWE of controls
Holla et al.	1999	Czech	Caucasian	Adults	189	141	34	94	61	162	216	37	75	29	149	133	0.4242
Kim et al.	2004	Korea	Asian	Adults	137	219	38	78	21	154	120	81	104	34	266	172	0.9484
Wang et al.	2005	China	Asian	Adults	69	101	27	29	13	83	55	44	41	16	129	73	0.2258
Ku et al.	2006	Taiwan	Asian	Children	75	66	36	35	4	107	43	36	27	3	99	33	0.4602
Lu et al.	2006	China	Asian	Adults	60	40	6	23	31	35	85	17	13	10	47	33	0.0372
Lue et al.	2006	Taiwan	Asian	Children	211	102	100	88	23	288	134	56	42	4	154	50	0.2549

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

Overall analysis

The main results of our meta-analysis under five distinct genetic models are listed in Table 2. In the overall analysis, the results showed that ACE I/D polymorphism had a statistically significant association with increased AR risk under all genetic models (Allele contrast: OR=1.46, 95% confidence interval (CI): 1.14–1.86, Figure 2; Homozygous comparison: OR=2.17, 95% CI: 1.29–3.67; Heterozygous comparison: OR=1.42, 95% CI: 1.11–1.81; Dominant model: OR=1.54, 95% CI: 1.22–1.94; Recessive model: OR=1.64, 95% CI: 1.22–2.21; p values of Z test about ORs analysis under all genetic models were less than 0.05).

Table 2.

Main results of pooled odds ratios (ORs) in this meta-analysis.

Study groups	n	D versus I		DD versus II		ID versus II		ID +DD versus II		DD versus II+ID
		OR (95% CI)	p _h	OR (95% CI)	p _h	OR (95% CI)	p _h	OR (95% CI)	p _h	OR (95% CI)	p _h
Total	6	1.46(1.14–1.86)	0.053	2.17(1.29–3.67)	0.087	1.42(1.11–1.81)	0.320	1.54(1.22–1.94)	0.124	1.64(1.22–2.21)	0.211
Ethnicity
Caucasian	1	1.49(1.10–2.04)	–	2.29(1.20–4.35)	–	1.36(0.78–2.38)	–	1.62(0.96–2.75)	–	1.84(1.11–3.06)	–
Asian	5	1.46(1.06–2.01)	0.030	2.20(1.09–4.42)	0.051	1.43(1.09–1.87)	0.211	1.52(1.18–1.97)	0.072	1.54(1.07–2.22)	0.151
Age
Children	2	1.35(0.99–1.84)	0.603	2.40(0.97–5.93)	0.366	1.21(0.81–1.81)	0.816	1.33(0.91–1.96)	0.926	2.30(0.96–5.47)	0.331
Adults	4	1.55(1.07–2.24)	0.015	2.19(1.10–4.34)	0.034	1.55(1.14–2.11)	0.176	1.67(1.25–2.23)	0.049	1.55(1.13–2.14)	0.130

CI: confidence interval; p_h: p-value of Q-test for heterogeneity test.

Figure 2.

Forest plot of allergic rhinitis AR risk associated with angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism by ethnicity stratification under allele contrast (D versus I). Random effects model was used. CI: confidence interval; OR: odds ratio.

Stratified analysis by ethnicity and age

In the subgroup analysis by ethnicity, significant elevated AR risks were associated with ACE I/D polymorphism in Asians under all genetic models (p<0.05) and in Caucasians under under allele contrast, homozygous comparison and recessive model (p<0.05) (Figure 2).

In the subgroup analysis by age, ACE I/D polymorphism was associated with significant elevated risks of AR in adults (p<0.05) but not in children (p>0.05) under all genetic models (Figure 3).

Figure 3.

Forest plot of allergic rhinitis (AR) risk associated with angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism by age stratification under allele contrast (D versus I). Random effects model was used. CI: confidence interval; OR: odds ratio.

Heterogeneity and publication bias

There were some significant heterogeneities under allele contrast (p=0.053) and homozygous comparison(p=0.087).Hence, the results under allele contrast were assessed under random effects model. Nevertheless, there were no significant heterogeneities under the other three genetic models (p>0.10), so the results were assessed under fixed effects model.

In this meta-analysis, we used both funnel plots, Begg’s test and Egger’s linear regression method to evaluate the publication bias. There were no obvious asymmetry in the funnel plots. Meanwhile, results of Begg’s test and Eggers’s linear regression method indicated that there were no obvious publication bias (p>0.05, Figure 4).

Figure 4.

Begg’s funnel plot with pseudo-95% confidence limits under allele contrast (deletion (D) versus insertion (I)).

Sensitivity analysis

Sensitivity analysis was performed to reflect the impact of the individual studies to the summarized ORs by removing one study each time in the repeated meta-analysis.

There was one study that significantly deviated from Hardy-Weinberg Equilibrium.²⁶ However, there were no material alterations on heterogeneities and results including ORs and 95% CIs after excluding this study. As a result, we included this study.

Among the included six studies, the study of Lu et al.²⁹ was found to be the major source of heterogeneities by sensitive analysis (Figure 5), and heterogeneities were substantially removed after excluding this study under allele contrast (I² =0%, p=0.823). (Before excluding, I² =54.2%, p=0.053). Nevertheless, the summarized ORs with 95% CIs under allele contrast were not significantly influenced (OR=1.32, 95% CI: 1.12–1.56, p=0.001). (Before excluding, OR=1.46, 95% CI: 1.14–1.86, p=0.003). Our results showed that the summarized ORs were not substantially altered, which indicated statistically obvious robustness in our results. Consequently, the study of Lu et al. was included.

Figure 5.

The result of sensitive analysis under allele contrast (deletion (D) versus insertion (I)). The combined OR with 95% CI is shown after the labeled study is excluded and the remaining studies are reanalyzed. The random effects model is adopted.

Discussion

It has been shown that the underlying mechanisms of AR comprise both genetic and environmental factors^30,31 and some inherited susceptibility genes with SNPs may exert their effects in AR development.^32,33

Up to now, several studies on the association between ACE I/D polymorphism and atopic disorders have been reported.^34–36 The mechanism underlying why the ACE I/D polymorphism affects susceptibility to atopic disorders is undetermined. There is ample evidence indicating that the ACE I/D polymorphism may modulate the expression of the ACE gene and the DD and D allele of the ACE gene which brings about higher plasma ACE levels and increased angiotensin II levels which are associated with many atopic disorders such as rheumatoid arthritis, asthma and nephrotic syndrome.^17,19,37 With regard to the correlation between genetic variants and AR susceptibility, different studies on the association between the ACE I/D polymorphism and AR risk have showed discrepancy in results.^23–28 Thus, our meta-analysis from six studies comprising 741 AR patients and 669 controls was performed to precisely assess the possible association of ACE I/D polymorphism with the susceptibility of developing AR.

Our meta-analysis, which comprised 741 AR patients and 669 controls, indicated the following: first of all, in the overall analysis, the ACE I/D polymorphism had a statistically significant association with increased AR risk under all genetic models; second, in the subgroup analysis by ethnicity, significant elevated AR risks were associated with ACE I/D polymorphism in Asians under all genetic models and in Caucasians under under allele contrast, homozygous comparison and recessive models; finally, in the subgroup analysis by age, the ACE I/D polymorphism was associated with significant elevated risks of AR in adults but not in children under all genetic models.

In addition, there were no material alterations (p>0.05 in the Z test of ORs) after excluding the study that did not fulfill HWE. Our results by overall analysis were not coincident with the results from the studies as stated above.^24,25,28 Actually, it was reasonable that the results from epidemiologic studies were not consistent with the results from respective functional study. This is because AR is a complex atopic disorder and is affected by many factors including both genetic and environmental factors, and different genetic backgrounds including age or ethnicity may lead to different outcomes^38,39 and other undiscovered genes involved in AR development might mask the influence of the D or I allele.

Some limitations of our study should be considered. First, the included studies were carried out mainly in Asians and adults, and only one study were performed in Europeans, only two studies in children, which increases the limitation of statistical power in the subgroup analysis with small sample sizes. Hence, studies with larger sample sizes and with sufficient large subgroups would be warranted to verify our findings. Second, we only included published papers, as a result there may be publication bias across studies, although Begg’s test and Egger’s linear regression method did not show any conspicuous publication bias. Thirdly, some significant heterogeneities across studies were detected under allele contrast and homozygous comparison in this meta-analysis. Nevertheless, this was not a principal issue because our results showed that the related summarized ORs were not substantially altered after excluding the study of Lu et al. which had been proved to be the main source of heterogeneities by sensitivity analysis (Figure 5), and this indicated statistically obvious robustness in our results. Finally, AR is an intricate atopic disorder comprising complex interactions of genes and environmental factors. ACE I/D polymorphism is only one phenotype of AR, and there are many other phenotypes and environmental factors that participate in the development of AR.^40,41 The data including confounding factors such as occupation, lifestyle, gender, a history of smoking, air pollution and other phenotypes are insufficient for further analysis in this study.

Overall, our results indicated that there were statistically significant associations of the ACE I/D polymorphism and susceptibility to AR, particularly when the cases were Asians or adults.

In conclusion, the ACE I/D polymorphism may be a risk factor for AR and studies with large sample sizes and representative populations are warranted to verify this finding.

Footnotes

Conflict of interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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