In the present study, our results indicated that there was no significant association between CHI3L1 rs4950928 polymorphism and asthma susceptibility in overall analyses. However, following subgroup analysis by ethnicity, there was a protective effect of CHI3L1 rs4950928 polymorphism on asthma risk in Caucasians. The G allele of CHI3L1 rs4950928 might be a protective factor against the development of asthma. As for association between CHIA rs10494132 polymorphism and asthma risk, no evidence was found in the overall population, while a significantly increased risk of asthma was found in Asians as well as in children of all ethnicities.

The gene CHI3L1, 10 exons long and located on chromosome 1q31-q32, codes for the chitinase-like protein YKL-40, which is a 40 kDa protein produced by cells in the airway mucosa, such as monocytes, macrophages and neutrophils [10, 17, 25]. YKL-40 binds with ubiquitously expressed chitin, but unlike chitinases CHIT1 and CHIA, which lacks measurable enzymatic chitinase activity [10]. Studies have shown that serum YKL-40 level is increased in patients with asthma and correlated with asthma severity, thickness of the subepithelial basement membrane, and pulmonary function, indicating that serum YKL-40 is an inflammatory biomarker associated with disease activity and mortality in asthmatic patients [12, 26]. Further study has shown that YKL-40 regulates TH2 immune response promoting airway inflammation in asthmatic mouse models as well as actives Akt, Erk, and p38 signaling pathway to promote human bronchial smooth muscle cell proliferation and migration, suggesting that YKL-40 is associated with the pathogenesis of asthma [27]. In addition, Genetic studies have demonstrated that the polymorphic variants of CHI3L1 gene contribute to the pathogenesis of asthma through influencing on airway inflammation and airway remodeling in the asthmatic patients [15, 26]. Recently, the relationship between CHI3L1 rs4950928 polymorphism and susceptibility to asthma was increasingly investigated [7, 18, 20, 21]. A Genome-wide Association Study (GWAS) reported by Ober et al. identified that the G allele of CHI3L1 rs4950928 is protective against asthma in three populations of European ancestry with mild asthma [18]. Another study have demonstrated that an association between CHI3L1 rs4950928 polymorphism and asthma is found, although the risk allele was opposite of that reported by Ober [21]. In contrast, additional publications have shown no significant association between genetic variation in the CHI3L1 rs4950928 and asthma risk [7, 20]. To date, the effect of genetic variation in CHI3L1 on asthma risk has not been fully addressed. Therefore, our meta-analysis provided a more statistical estimation demonstrating the relationship between CHI3L1 rs4950928 polymorphism and risk of asthma.

Our meta-analysis synthesized a total of 1062 cases and 1034 controls from 5 eligible studies to analyze the association between CHI3L1 rs4950928 polymorphism and asthma risk. The pooled results indicated no significant association between CHI3L1 rs4950928 polymorphism and asthma susceptibility. After stratified population by ethnicity, analysis indicated that the G allele of CHI3L1 rs4950928 had a reduced risk for asthma in Caucasians. No subgroup analysis was performed in Asians and Africans due to only 1 study included in Asians and Africans. When stratified population by age, the results remained non-significant in children. We could not perform analysis in adults since only one study was included.

The gene for CHIA is present on chromosome 1q13.1–21.3 and produces acid mammalian chitinase, which is a 50 kDa acid-stable protein [13]. Study has observed that serum CHIA level is overexpressed in ovalbumin-induced mouse model of asthma [16]. In addition, inhibition of CHIA expression reduced TH2-dependent airway inflammation, bronchial hyper-reactivity, and eosinophil counts in these asthma mouse model [16]. In humans, the expression of CHIA is strongly upregulated in lungs of asthmatic patients [16]. Furthermore, the CHIA enzyme has been found to be a downstream protein of interleukin-13, a cytokine implicated in the effect of human asthma [16]. Therefore, the CHIA enzyme has been suggested to be a positive mediator involved in the pathogenesis of asthma. Whereas, conflicting findings regarding its physiological role in asthma have reported that CHIA can inhibit chitin-induced allergic innate immune response in a mouse model by inhibiting eosinophil and basophil recruitment to the lungs [28]. Recently, one genetic study has described exonic CHIA polymorphisms are associated with bronchial asthma in a German pediatric population, indicating that exonic CHIA gene may be under the control of regulatory regions [19]. One promoter SNP, rs10494132, has been reported to be associated with pediatric asthma in Chinese population [23]. However, another three studies has demonstrated that no relationship between CHIA rs10494132 variation and risk of asthma is found [8, 22, 24]. Here we have performed meta-analysis to examine its association with asthma risk.

In this meta-analysis, 796 cases and 744 controls in 4 published articles were included. Results suggested that there was no significant relationship between CHIA rs10494132 polymorphism and asthma susceptibility. When population was stratified based on ethnicity, a positive correlation between CHIA rs10494132 polymorphism and asthma risk was found in Asians. No subgroup analysis was performed in Caucasians due to limited studies included. Moreover, in the subgroup analysis conducted according to age, CHIA rs10494132 variant was also found to be associated with the increased risk of asthma in children. We could not perform subgroup analysis in adult group duo to insufficiency of relevant studies included.

There are several limitations in this meta-analysis. Firstly, sample size in this meta-analysis was small, which might result in bias of the results when evaluating the association of CHI3L1 and CHIA gene polymorphisms with susceptibility to asthma. Secondly, the original data in some studies was lacking, which might limit sufficient statistical power to evaluate the potential effects of gene-gene and gene-environment interactions on the development of asthma. Thirdly, significant between-study heterogeneity was found in some pooled analyses. The exact sources of heterogeneity by meta-regression analysis were unable to further identify because of limited relevant data provided. Subgroup analysis was further performed based on ethnicity and age. However, heterogeneity was not resolved, indicating that other potentially relevant factors such as gender, genotyping method, phenotype of the disease may account for the heterogeneity. Fourthly, asthma is a heterogeneous disease with various genotypes and phenotypes. Although a genetic basis for asthma is undeniable, only a small proportion of heritability can be explained by the previously identified genetic polymorphisms associated with asthma because of the variability of the clinical phenotype. At last, only published studies were retrieved in the meta-analysis and possible publication bias might exist, despite no statistically significant publication bias was detected by Begg’s test or Egger’s test.