Interleukin-16 Polymorphism Is Associated with an Increased Risk of Glioma

Introduction

Glioma is the most common primary brain tumor in humans and accounts for more than 40% of the newly diagnosed brain tumors, resulting in poor prognosis (Ohgaki and Kleihues, 2005; Van Meir et al., 2010; Jemal et al., 2011; Ostrom and Barnholtz-Sloan, 2011). Therefore, identification of risk factors that influence the development of glioma is helpful for early diagnosis and prevention of the disease. Although the etiology of glioma is not fully known, current evidence has shown that ionizing irradiation is an environmental risk factor for glioma. However, not all individuals exposed to ionizing irradiation will develop glioma, suggesting that genetic variants might play a key role in modifying the risk of glioma.

Interleukin (IL)-16 is a cytokine that has been characterized as a lymphocyte chemoattractant factor (Center and Cruikshank, 1982). Signaling of IL-16 is mediated by binding to the CD4 molecule. Moreover, IL-16 has been demonstrated to recruit and activate many other cells expressing the CD4 molecule, including monocytes, eosinophils, and dendritic cells (Cruikshank et al., 1994; Center et al., 1996). In the human brain, IL-16 is expressed by a subpopulation of microglial cells (Mittelbronn et al., 2001), which might be a valuable marker for the detection of microglia development and activation in nonmalignant central nervous system pathologies (Schwab et al., 2001; Guo et al., 2004). In addition, IL-16 immunoreactivity is detected in human and rat gliomas, and the upregulation of IL-16 expression correlates with malignancy of tumors, indicating that IL-16 might play a role in the regulation of the local inflammatory milieu and tumor progression in both human and experimental astrocytomas (Liebrich et al., 2007).

Recently, several studies have been conducted to assess single-nucleotide polymorphisms (SNPs) in the IL-16 gene for the association with cancer susceptibility, including colorectal cancer, gastric cancer (Gao et al., 2009b; Azimzadeh et al., 2011, 2012; Zhang and Wang, 2013), prostate cancer (Batai et al., 2012), hepatocellular carcinoma (Li et al., 2011), renal cell carcinoma (Zhu et al., 2010), and nasopharyngeal carcinoma (Gao et al., 2009a; Qin et al., 2013). To date, no report was done to evaluate the effect of IL-16 polymorphisms on glioma risk. In this study, we carried out an association study to assess whether IL-16 polymorphisms were associated with the susceptibility to glioma in a Chinese population.

Materials and Methods

Results

The characteristics of study subjects are shown in Table 1. The cases and controls were similar in age and gender. All of the three SNPs (i.e., rs4778889, rs11556218, and rs4072111) are in HWE in the control subjects. The association between the SNPs and the risk of glioma is summarized in Table 2. We found that the rs11556218TG genotype is associated with an increased risk of glioma compared with the TT genotype (OR=1.76; 95% CI, 1.22-2.54; p=0.002). Similarly, the rs11556218G allele is associated with an increased risk of glioma compared with the T allele (OR=1.41; 95% CI, 1.06-1.87; p=0.017). However, no significant association was observed between the IL-16 rs4778889 and rs4072111 polymorphisms and the risk of glioma.

Discussion

To the best of our knowledge, this is the first study to investigate the relationship between the IL-16 polymorphisms and the occurrence of glioma in a Chinese population. We found that the rs11556218TG genotype had a 1.76-fold increased risk of developing glioma compared with the TT genotype. Moreover, patients carrying the rs11556218G allele had a 1.41-fold increased risk for developing glioma compared to individuals carrying the T allele. These findings indicate that the IL-16 rs11556218 polymorphism may be used as a susceptibility marker for glioma.

Increasing evidence has shown that inflammation contributes to the process of tumor development and progression (Moss and Blaser, 2005; Lu et al., 2006; Chi et al., 2012; Wang et al., 2012; Balgkouranidou et al., 2013). Human herpesvirus 6 latent infection is related to glioma through promotion of the secretion of IL-6, IL-8, tumor necrosis factor α (TNF-α), and transforming growth factor β (Chi et al., 2012). IL-6 and TNF-α can also be stimulated to be secreted by inflammatory cells activated by IL-16 after binding to CD4. It has been identified that IL-16 is upregulated in cutaneous T-cell lymphoma as well as in human and experimental brain tumors (Blaschke et al., 1999; Liebrich et al., 2007). Furthermore, higher serum levels of IL-16 were observed in several malignant cancers (Kovacs, 2001; Koike et al., 2002; Gao et al., 2009b). Taken together, these findings donate that IL-16 plays an important role not only in inflammation but also in tumorigenesis.

In 2000, Nakayama et al. (2000) first identified a −295 T>C polymorphism (rs4778889) in the promoter region of the IL-16 gene, and the −295C allele had a sixfold increased transcription activity compared with the −295T allele (Burkart et al., 2006). Because the polymorphism is functional, several association studies have been conducted to examine the IL-16 rs4778889 polymorphism on cancer risk. In the current study, we failed to find any association between the IL-16 rs4778889 polymorphism and the susceptibility to glioma. Our results were consistent with the findings reported by Gao et al. (2009a, 2009b), who found no association between the IL-16 rs4778889 polymorphism and the risk of colorectal cancer and nasopharyngeal carcinoma in a Chinese population. In contrast, Azimzadeh et al. (2011) reported that the IL-16 rs4778889 polymorphism was associated with a decreased risk of colorectal cancer in Iranian male subjects. Zhu et al. (2010) reported that the IL-16 rs4778889 polymorphism was associated with an increased risk of developing renal cell carcinoma in a Chinese population. Zhang and Wang (2013) reported that the rs4778889 CC genotype was significantly associated with a 1.97-fold increased risk of noncardia gastric cancer. A possible reason for the discrepancy may be that the IL-16 gene plays a different role in different tumorigenesis.

Recently, an association between the rs11556218 polymorphism and cancer risk has been extensively studied. Li et al. (2011) reported that the rs11556218 TG and GG genotypes were associated with significantly increased risks of HBV-related hepatocellular carcinoma compared with the TT genotype. Batai et al. (2012) reported that the rs11556218 polymorphism was strongly associated with the risk of prostate cancer. Moreover, some authors reported that the rs11556218TG genotype was associated with a significantly higher risk of colorectal cancer, gastric cancer, and nasopharyngeal carcinoma (Gao et al., 2009a, 2009b; Qin et al., 2013). In agreement with the results, we found a positive association of the rs11556218TG genotype with a 1.76-fold increased risk of glioma.

Although the positive association between the IL-16 polymorphism and glioma risk was observed, we cannot rule out chance findings due to the relatively small sample size. In addition, the control subjects in our study were hospital based. Thus, the population-based studies with a larger sample size are still needed.

In conclusion, we demonstrated that the IL-16 rs11556218 polymorphism had an increased risk to develop glioma in a Chinese population, which offers important insights into the etiology of glioma. Further studies with larger sample sizes are warranted.