The data were independently gathered in duplicate by two investigators on the basis of a standard protocol (Y.M.L. and L.F.C.). Discrepancies between the investigators were settled by discussion until consensus was reached. Literature databases were searched, including PubMed, Google Scholar and the China National Knowledge Infrastructure (CNKI) databases. The following key words and subject terms were searched: ‘RANTES’, ‘−403G/A’, ‘−28C/G’, ‘pediatric asthma’ and ‘gene polymorphism’. The reference lists of retrieved reviews and articles were hand-searched. The search was without restriction on language and was conducted on human subjects. The literature search was updated on 30 May 2012.

The titles and abstracts of all citations identified by the literature search were reviewed. Selection criteria were then applied to all potentially relevant studies. The selection criteria for inclusion in the meta-analysis were: i) case-control studies conducted to evaluate the association between RANTES gene polymorphisms (−403G/A and −28C/G) and pediatric asthma risk; ii) sufficient genotype data were presented to calculate the odds ratios (ORs) and 95% confidence intervals (CIs); iii) the study should clearly describe pediatric asthma diagnoses and the sources of cases and controls. Studies were excluded when: i) they were non-case-control studies that evaluated the association between RANTES gene polymorphisms and pediatric asthma risk; ii) they were case reports, letters, reviews or editorial articles; iii) they were studies based on incomplete raw data and no usable data were reported; iv) they contained duplicate data.

The following characteristics were collected from each study: first author, year of publication, region of the first or corresponding author, ethnicity, number of cases and controls, number of genotypes and evidence of Hardy-Weinberg equilibrium (HWE; Table I). Ethnicities were classified as Asian or Caucasian. If original genotype frequency data were unavailable in the relevant articles, an email was sent to the corresponding author for additional data. For conflicting evaluations, an agreement was reached following a discussion.

A meta-analysis was performed using the STATA package version 12.0 (Stata Corporation, College Station, TX, USA). The OR corresponding to the 95% CI was used to assess the intensity of the association between RANTES gene polymorphisms (−403G/A and −28C/G) and pediatric asthma under a homozygote comparison (AA vs. aa), a heterozygote comparison (AA vs. Aa), a dominant model and a recessive mode between groups. In the current study, the dominant model was defined as Aa+aa vs. AA, where ‘A’ and ‘a’ are major and minor alleles, respectively, and the recessive model as aa vs. AA+Aa. The distribution of genotypes in the included studies was tested for HWE using the χ² test. The effect of heterogeneity by the Q-test and I² test was also quantified. I2 ranges between 0 and 100% and I² values of 25, 50 and 75% were defined as low, moderate and high estimates, respectively. When a significant Q-test (P<0.10) or I²>50% indicated heterogeneity across studies, the random-effects model was used for meta-analysis, otherwise the fixed-effects model was calculated. Sensitivity analysis was performed to assess the stability of the results by excluding the study by Sohn et al (16) with genotype distributions not in HWE. Begg’s test was used to provide evidence of publication bias, shown as a funnel plot. P<0.05 was considered to indicate a statistically significant result.

There were 287 studies relevant to the search words. Through screening the title and reading the abstract and the entire article, 7 eligible articles were selected for this meta-analysis (Fig. 1). All the studies were case-control studies that evaluated the association between RANTES gene polymorphisms and pediatric asthma risk (11–17). For −28C/G, the sample population in the Europe group was inadequate and ethnicity-specific meta-analysis was not conducted on Caucasians. The HWE test was performed on the genotype distribution of the controls in all included studies; all of them were in HWE except that in the study by Sohn et al (16). The main characteristics of the included studies are listed in Table I.

A summary of the meta-analysis findings of the association between RANTES gene polymorphisms (−403G/A and −28C/G) and pediatric asthma risk is shown in Table II. Meta-analysis results showed that there was no association between the −403G/A polymorphism and the risk of pediatric asthma, the meta-analysis indicated that the −28C/G polymorphism was associated with an increased risk of pediatric asthma in the general population (recessive model: OR, 1.34; 95% CI, 1.04–1.72). On the basis of the potential overestimation of the true effect of the polymorphism on the pediatric asthma risk, these studies were stratified according to ethnicity. In the stratified analysis, no significant associations were identified in Asian and European populations. Sensitivity analysis was performed to assess the stability of the results by excluding one study by Sohn et al (16) with genotype distributions not in HWE and the exclusion of any single study did not alter the significance of the final decision, suggesting that the outcomes were robust. The funnel plot and Begg’s test were used to assess the publication bias. There was no evidence of publication bias visually from the funnel plot (Fig. 2, Table II). The difference was not significant in Begg’s test (all P>0.05), suggesting that the publication bias was low in the present meta-analysis.