Non-Association of IL-16 rs 4778889 T / C Polymorphism with Cancer Risk in Asians : a Meta-analysis

Cancer is a major worldwide public health problem. It has been reported to give rise to approximately 12.7 million new cases and 7.6 million deaths in 2008 (Ferlay et al., 2008). The pathogenesis of cancer is a multistep and multifactorial process resulting from complex interactions between environmental and genetic factors (Pharoah et al., 2004). There is obvious evidence that inflammation is a risk factor for tumor development (Chow et al., 2012; Kundu et al., 2012). IL-16 is considered a pro-inflammatory cytokine and plays an important role in inflammatory diseases as well as in carcinogenesis. IL-16 can activate CD4+ T cells, monocytes, macrophages and dendritic cells by binding to the CD4 molecule (Cruikshank et al., 1994; Center et al., 1996). Furthermore, IL16 can stimulate the secretion of different inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), IL1b, IL6 and IL15, which are associated with carcinogenesis (Mathy et al., 2000). The gene encoding IL-16 cytokine is located on chromosome 15q26.3 in the human genome (Kim et al., 1999). Numerous studies have investigated the potential association of IL-16 rs4778889 T/C polymorphism and cancer risk (Gao et al., 2009; Gao et al., 2009; Zhu et al., 2010; Azimzadeh et al., 2011; Li et al., 2011). However, a single study might have been underpowered to detect the overall effects, and the genetic epidemiological studies into cancer risk are conflicting. Therefore, we performed


Introduction
Cancer is a major worldwide public health problem. It has been reported to give rise to approximately 12.7 million new cases and 7.6 million deaths in 2008 (Ferlay et al., 2008). The pathogenesis of cancer is a multistep and multifactorial process resulting from complex interactions between environmental and genetic factors (Pharoah et al., 2004). There is obvious evidence that inflammation is a risk factor for tumor development (Chow et al., 2012;Kundu et al., 2012).
IL-16 is considered a pro-inflammatory cytokine and plays an important role in inflammatory diseases as well as in carcinogenesis. IL-16 can activate CD4+ T cells, monocytes, macrophages and dendritic cells by binding to the CD4 molecule (Cruikshank et al., 1994;Center et al., 1996). Furthermore, IL16 can stimulate the secretion of different inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), IL1b, IL6 and IL15, which are associated with carcinogenesis (Mathy et al., 2000). The gene encoding IL-16 cytokine is located on chromosome 15q26.3 in the human genome (Kim et al., 1999).
Numerous studies have investigated the potential association of IL-16 rs4778889 T/C polymorphism and cancer risk Zhu et al., 2010;Azimzadeh et al., 2011;Li et al., 2011). However, a single study might have been underpowered to detect the overall effects, and the genetic epidemiological studies into cancer risk are conflicting. Therefore, we performed

Non-Association of IL-16 rs4778889 T/C Polymorphism with Cancer Risk in Asians: a Meta-analysis
Lin-Lin Xu 1 , Zhi-Chun Song 2 , Kun Shang 3 , Li-Qin Zhao 4 , Zhan-Sheng Zhu 5 * a comprehensive meta-analysis to derive a more precise estimation of the relationship between IL-16 rs4778889 T/C polymorphism and the risk of cancer.

Publication search
A comprehensive literature search was performed using PubMed, Embase and Web of Science databases for relevant articles (up to November 20, 2013) with the following key words "IL-16", "polymorphism" and "cancer". In addition, references of retrieved articles were also screened.

Inclusion criteria
Studies included in this meta-analysis had to meet the following criteria: (1) an evaluation of the associations between IL-16 rs4778889 T/C polymorphism and cancer risk; (2) case-control studies; (3) detailed genotype data for estimating of odds ratio (OR) and 95% confidence interval (CI); and (4) the distribution of genotypes among controls are in Hardy-Weinberg equilibrium (P>0.05). If multiple studies had overlapping or duplicate data, only those with complete data were included.

Data extraction
Data were independently evaluated and extracted from the relevant papers by two of the authors (XLL and SZC). Any disagreement was resolved by discussion with a third Lin-Lin Xu et al author (ZZS). The following information was collected from each article: first author, publication year, country, ethnicity, source of controls, genotyping method, the number of cases and controls, and genotype distribution of cases and controls.

Statistical analysis
HWE was evaluated for controls in each study by the Chi-square test and p<0.05 was considered as departure from HWE. A χ 2 -based Q-test examined the heterogeneity between each study. If p<0.05 for Q-test suggested significant heterogeneity, and the random-effects model was conducted to calculate the pooled OR; Otherwise, the fixed-effects model was used. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association between IL-16 rs4778889 T/C polymorphism and cancer risk. Sensitivity analysis was performed to identify the effect of data from each study on the pooled OR. Finally, Begg's funnel plots and Egger's test were carried out to evaluate publication bias of literatures (Begg et al., 1994;Egger et al., 1997). All analyses were done with RevMan 5.0 and STATA12.0 software.

Study characteristics
A flow chart of the study selection procedure is shown in Figure 1. A total of 31 publications from PubMed, Embase and Web of Science databases were reviewed. After a review of titles, abstracts and articles, 6 studies with 1,603 cases and 2,342 controls were included in this meta-analysis.
The main characteristics of the included studies are listed in Table 1. All included studies were carried out in Asian population. As for cancer type, there were four studies focusing on digestive cancer consisted of colorectal cancer, gastric cancer and hepatocellular carcinoma, and two studies focusing on colorectal cancer. In addition, the genotype distribution in the controls was in agreement with HWE test in all included studies.

Quantitative synthesis
Results of the meta-analysis are shown in Table 2 (Figure 2). Furthermore, in the subgroup analysis by cancer type, results also indicated that IL-16 rs4778889 T/C polymorphism was not associated with digestive cancer including colorectal cancer (Table 2).

Sensitivity analysis and Publication bias
The OR was no statistical difference when excluding every single study by sequence and the result showed that no individual study significantly affected the pooled OR, suggesting stability of this meta-analysis. Begg's funnel plots and Egger's test were performed to assess the potential publication bias in the available literature. The shapes of Begg's funnel plots did not reveal any evidence of obvious asymmetry (Figure 3). In addition, the result of Egger's test also did not show evidence of publication bias (CC vs. CT+TT: P=0.28; CC+CT vs. TT: P =0.84; CC vs. TT: P =0.37; CT vs. TT: P =0.59; C vs. T: P =0.97).

Discussion
To our knowledge, this is the first meta-analysis which comprehensively assessed the associations between rs4778889 T/C polymorphism of the IL-16 gene and cancer risk. In this study, rs4778889 T/C polymorphism was investigated, and a total of six case-control studies were included. The results showed that IL-16 rs4778889 T/C polymorphism was not associated with the risk of cancer.
The findings in current meta-analysis should be interpreted with caution because of several limitations. Firstly, our results were based on unadjusted estimates, while a more precise analysis could be conducted if individual data were available. Secondly, a relatively small number of studies and subjects were included, which may reduce the statistical power of the analysis. Thirdly, although the statistical data did not reflect publication bias, potentially publication bias will be existed in our results because studies reporting positive findings are more likely to be published than those reporting negative results.
In conclusion, this meta-analysis suggested that IL-16 rs4778889 T/C polymorphism was not associated with the risk of cancer. In addition, our results also demonstrated IL-16 rs4778889 T/C polymorphism was not associated with the risk of digestive cancer including colorectal cancer. However, large and well-designed studies are warranted to validate our findings.