154 593 –600 © The Authors 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320313502107 jra.sagepub.com Introduction Allergic rhinitis AR is a comp
Trang 1Journal of the Renin-Angiotensin-Aldosterone System
2014, Vol 15(4) 593 –600
© The Author(s) 2013 Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320313502107 jra.sagepub.com
Introduction
Allergic rhinitis (AR) is a complex immunoglobulin (Ig)
E-mediated atopic disease affecting approximately 10–
30% of the general population, especially in
industrial-ized 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
evi-dence suggesting that AR is a complex multifactorial
dis-order including both genetic and environmental factors4–8
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
angi-otensin I into angiangi-otensin 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
Angiotensin-converting enzyme insertion/
deletion polymorphism associated with
allergic rhinitis susceptibility: Evidence
from 1410 subjects
Hai Lin1,*, Dong Lin2,* and Chun-Quan Zheng1
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
represen-tative population are warranted to verify this finding
Keywords
Angiotensin-converting enzyme, insertion/deletion gene polymorphism, meta-analysis, allergic rhinitis
1 Department of Otorhinolaryngology, Eye and ENT Hospital of Fudan University, China
2 Department of Biology and Chemical Engineering, Fuqing Branch of Fujian Normal University, China
* These authors contributed equally to this work.
Corresponding author:
Chun-Quan Zheng, Department of Otorhinolaryngology, Eye and ENT Hospital of Fudan University, Shanghai 200031, China
Email: 96zheng@gmail.com
Original Article
Trang 2594 Journal of the Renin-Angiotensin-Aldosterone System 15(4)
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
inconsist-ent Several papers have reported that a statistically
signifi-cant correlation was found between ACE I/D SNP and AR
risk.23,26,27 Conversely, the results from other studies
sug-gested 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
cri-teria 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
distribu-tion 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
categori-zation 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
hetero-geneity less than 0.1 was confirmed as statistically signifi-cant 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 per-form 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 anal-yses by ethnicity and age stratification In addition, sensi-tivity 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 rele-vant 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 per-formed subgroup analysis by ethnicity and age stratifi-cation Details of the subjects in these studies are outlined in Table 1
Overall analysis
The main results of our meta-analysis under five distinct genetic models are listed in Table 2 In the overall analy-sis, the results showed that ACE I/D polymorphism had a statistically significant association with increased AR risk
Trang 3under 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)
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
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.
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) ph OR (95% CI) ph OR (95% CI) ph OR (95% CI) ph OR (95% CI) ph
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; ph: p-value of Q-test for heterogeneity test.
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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)
Heterogeneity and publication bias
There were some significant heterogeneities under allele
con-trast (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).
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 sen-sitive analysis (Figure 5), and heterogeneities were sub-stantially 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 exclud-ing, 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
Discussion
It has been shown that the underlying mechanisms of AR comprise both genetic and environmental factors30,31 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
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
Trang 5the 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
pos-sible association of ACE I/D polymorphism with the sus-ceptibility 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 statisti-cally significant association with increased AR risk under all genetic models; second, in the subgroup analysis by eth-nicity, 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
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.
Figure 4 Begg’s funnel plot with pseudo-95% confidence limits under allele contrast (deletion (D) versus insertion (I))
logor: logarithm of odds ratios; s.e.: standard error
Trang 6598 Journal of the Renin-Angiotensin-Aldosterone System 15(4)
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
epidemio-logic studies were not consistent with the results from
respec-tive 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
outcomes38,39 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
war-ranted 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
publica-tion bias Thirdly, some significant heterogeneities across
studies were detected under allele contrast and
homozy-gous 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 pol-lution 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 repre-sentative populations are warranted to verify this finding
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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