Association between RANTES Gene Polymorphisms and Asthma: A Meta-Analysis

Background A few recent studies have suggested that regulated on activation, normal T cell expressed and secreted (RANTES) polymorphisms (−403 G/A, −28C/G) are associated with asthma. However, there still existed studies which did not confirm these correlations. Objective The objective of this study was to evaluate the relationship of RANTES and asthma using a meta-analysis. Methods Pubmed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Results Eighteen studies were enrolled, including a total of 2558 cases and 2630 controls of −403 G/A, as well as 3311 cases and 4031 controls of −28C/G in this meta-analysis. The overall ORs and 95% CIs of −403 G/A were 1.19, 1.06–1.33 (P<0.001) and 1.25, 1.03–1.51 (P = 0.933) in dominant and recessive models, respectively. The overall ORs and 95% CIs of −28G were 1.23, 1.09–1.39 (P = 0.221) and 1.76, 1.32–2.34 (P = 0.356) in dominant and recessive models, respectively. No publication bias among studies was showed. Conclusions This meta-analysis showed that RANTES −403 G/A polymorphism was a risk factor for asthma, while −28C/G polymorphism were not associated with asthma.


Introduction
Asthma is a common chronic respiratory inflammation disease associated with airway hyperreactivity, reversible airway obstruction, mucus hypersecretion, inflammatory cell migration, bronchial epithelial desquamation, and airway wall remodeling [1,2]. It is a complex disorder caused by both genetic and environmental factors. Over 100 genes have been reported to be associated with asthma risk and related phenotypes [3,4].
The regulated on activation, normal T cell expressed and secreted (RANTES), a member of the CC chemokine family, is a potent eosinophil, monocyte, basophile and lymphocyte chemoattractant. It had close correlations with the attraction and recruitment of lymphocytes, monocytes, basophils and eosinophils to the places of inflammation, and thus, was involved in various inflammatory and immune disorders, including asthma [5,6,7]. Two RANTES promoter polymorphisms of 2403 G/A and 2 28C/G were demonstrated to affect the promoter activity and increase the expression of RANTES [8].
Although numerous studies have demonstrated the correlation between RANTES (2403G/G and 228C/C) polymorphisms and asthma, the results still remains inconsistent. Therefore, this metaanalysis was performed currently to observe the association of these two polymorphisms with asthma risk, which firstly provided the updated meta-analysis of comprehensive studies about RANTES gene polymorphisms and asthma.

Search strategy
Two independent reviewers searched Pubmed, Embase, and Cochrane library databases systemically and extensively to obtain the case-control genetic association of RANTES polymorphisms and asthma studies without any language restrictions. The Medical Subject Heading (MeSH) and keyword terms ''RANTES'', ''CCL5'', ''asthma'', and ''polymorphism'' were used as search criteria.

Study selection and data abstraction
The inclusion criteria for the gene association studies in this meta-analysis were as follows: 1) case-control studies and cohort studies; 2) original data on genotype and allele distributions and frequencies were available for case and control subjects; 3) genotype distributions of the controls were in Hardy-Weinberg equilibrium. Data abstraction was performed by two independent reviewers as mentioned above.

Statistical analysis
Chi-square test was used to determine whether the genotype distributions of the controls were in Hardy-Weinberg equilibrium. Heterogeneity between studies was tested with both Cochran's test and I 2 statistics. P,0.1 or I 2 .50% indicated significant heterogeneity in this study [9]. Publication bias was assessed by funnel plot and Egger's regression test [10]. Data of this meta-analysis were analyzed by Stata software (Version 12.0; Stata Corporation, College Station, TX). P-value ,0.05 were considered statistically significant.
We compared the minor allele to major allele in dominant, recessive, and additive models. The overall ORs and 95% CIs of

Discussion
Data of this meta-analysis showed that RANTES 2403 G/A polymorphism was a risk factor for asthma, while 228C/G polymorphism were not associated with asthma.
RANTES, also known as C-C motif chemokine ligand 5 (CCL5), is a potent chemoattractant which play an important role in immune and inflammatory regulation process. The RANTES gene is located on chromosome 17q11.2-q12, which is composed of three exons and two introns. It was reported that RANTES gene polymorphisms could influence the activity of transcription and protein expression in human [30]. Significantly elevated concentrations of RANTES were observed in asthmatic patients, and associated with asthma severity, demonstrating the important role of RANTES in the pathogenesis of this disorder [31,32,33]. Serum RANTES may a helpful noninvasive and diagnostic marker for monitoring asthma severity. Identification and blocking of RANTES and/or its receptor may be a promising therapeutic approach to asthmatic patients [34]. Previous investigations have reported the association of RANTES gene polymorphisms (2 403G/A and 228C/G) and asthma susceptibility, however, findings of the possible relationships are remain inconsistent.
In Chinese asthmatic children population, Leung et al. [17] found that RANTES 2403G/A polymorphism was associated with allergen sensitization and forced expiratory volume in 1-s (FEV 1 ), and no relation was observed in 228C/G polymorphism. On the contrary, numerous observations [14,20,28] reported opposite conclusions showing that 228C/G polymorphism may exacerbate asthma severity. In contrast to these results, neither 2 403G/A nor 228C/G was indicated to be associated with asthma [11,21].
In other countries, both 2403G/A and 228C/G polymorphisms did not have a detectable effect on asthma susceptibility in African Americans, Lebanon, Spanish or Budapest population, respectively [12,18,25,27]. However, Lachheb et al. [23] suggested that both polymorphisms may play an important role in asthma predisposition, airway obstruction severity, or bronchial hyperresponsiveness among Tunisian or Korean children. Moreover, several investigations also demonstrated either 2403G/A or 2 28C/G was related to asthma risk [16,19,29].
In this present study, we found that RANTES 2403 G/A polymorphism was a risk factor for asthma susceptibility under dominant genetic model, indicating its potential role in asthma pathogenesis. In the meanwhile, the data also indicated that 2 28C/G polymorphism was not associated with asthma risk. Furthermore, no publication bias among studies was showed. Up to now, there were four meta-analysis investigations indicating controversial results about the correlation between these two polymorphisms and asthma. Three studies about the association of RANTES gene polymorphisms and asthma susceptibility reported that 228C/G polymorphism could increase the risk of asthma in Asian children or pediatric asthma in global population, while no relationship was found in 2403G/A [35,36,37]. However, Zhang et al. [38] observed contrary findings showing that 2403G/A polymorphism would be a risk factor among atopic asthma patients, and no such association was indicated in 228C/G, which is consistent with our findings. Compared with previous studies, our present study firstly provided the updated meta-analysis of comprehensive studies about RANTES gene polymorphisms and asthma.
The susceptibility of asthma might be due to the interactions of various genes (including linkage among gene polymorphisms), environment and ethnic heterogeneity factors. Therefore, larger scale studies are required to provide confirm evidence on the roles of RANTES (2403A/G and 228C/G) polymorphisms in asthma risk.

Conclusions
In summary, we concluded that RANTES 2403 G/A polymorphism was a risk factor for asthma, while 228C/G polymorphism were not associated with asthma.