GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 18, Number 10, 2014 ª Mary Ann Liebert, Inc. Pp. 711–714 DOI: 10.1089/gtmb.2014.0170
SHORT REPORT
Interleukin-16 Polymorphism Is Associated with an Increased Risk of Glioma Qi-Sheng Luo,1,* Jun-Li Wang,2,* Yuan-Yang Deng,1 Hua-Dong Huang,1 Huang-De Fu,1 Chuan-Yu Li,1 and Hai-Neng Huang1
Objective: Previous studies have shown that interleukin (IL)-16 is overexpressed in human and rat gliomas. Potential links between IL-16 polymorphisms and glioma risk are currently unclear. The aim of this study was to investigate the association between IL-16 polymorphisms and glioma risk. Methods: We examined IL-16 gene polymorphisms (i.e., rs4778889, rs11556218, and rs4072111) in 216 patients with glioma and 275 controls in a Chinese population. Genotypes were determined using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were used to evaluate the effect of the IL-16 polymorphisms on glioma risk. Results: 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. Conclusion: These findings suggest that the IL-16 rs11556218 polymorphism may be used as a susceptibility marker for glioma.
Introduction
G
lioma 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.
1 Department of Neurosurgery and 2Center of Clinical Laboratory, Affiliated Hospital of Youjiang Medical College for Nationalities, Guangxi, Baise, People’s Republic of China. *These authors contributed equally to this work.
711
712
LUO ET AL. Genotyping
Table 1. Characteristics of Study Subjects Controls, n = 275
Variables
Age (years) 44.4 – 12.5 Gender (%) Male 155 (56.4) Female 120 (43.6) WHO grade (%) I-II — III-IV —
Patients with glioma, n = 216
p-Value
45.0 – 16.1
NS
123 (56.9) 93 (43.1)
NS
120 (55.6) 96 (44.4)
Genomic DNA was extracted from peripheral blood samples with an extraction kit (Qiagen, Chastworth, CA). IL-16 polymorphism genotyping was performed using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. Primers for amplification and restriction enzymes were described previously (Gao et al., 2009b). Statistical analyses
NS, no significance.
Materials and Methods Study population
The hospital-based case–control study was conducted in the hospital. A total of 491 subjects, including 275 controls and 216 patients with gliomas were recruited in this study between June 2010 and July 2013. Histological diagnosis and grading of tumors were performed according to the World Health Organization standards (Louis et al., 2007). The patients with a self-reported history of cancer were excluded. Control subjects were randomly selected from the general health check-up division of the hospital during the same time period. We excluded those participants who had central nervous system-related diseases or a history of cancer. The mean age – standard deviation was 44.4 – 12.5 in controls and 45.0 – 16.1 in cases, respectively. All cases and controls enrolled in this study were genetically unrelated Han Chinese from Baise and its surrounding regions. There was no difference according to age, gender, and living area between cases and controls. The approval to conduct this study was granted by the ethics committee of the hospital, and written informed consent was provided by all subjects.
All statistical analyses were performed using the Statistical Package for the Social Sciences software version 13.0 (SPSS, Chicago, IL). The chi-square and Student’s t-tests were used to test differences of sociodemographic factors between cases and controls. Genotypic distributions in controls for each SNP were tested for departure from the Hardy–Weinberg equilibrium (HWE) using the chi-square test. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were used to evaluate the effect of the IL-16 polymorphisms on glioma risk. A p value < 0.05 was considered statistically significant. 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.
Table 2. Genotype Distributions of IL-16 Polymorphisms Between Cases and Controls Polymorphisms rs4778889 T/C TT CT CC T allele C allele rs11556218 T/G TT TG GG T allele G allele rs4072111 C/T CC CT TT C allele T allele
Controls, n = 275 (%)
Gliomas, n = 216 (%)
OR (95% CI)
165 99 11 429 121
(60.0) (36.0) (4.0) (78.0) (22.0)
142 68 6 352 80
(65.7) (31.5) (2.8) (81.5) (18.5)
1.00 0.80 0.63 1.00 0.81
(Ref) (0.55–1.17) (0.23–1.76) (Ref) (0.59–1.11)
152 114 9 418 132
(55.3) (41.5) (3.3) (76.0) (24.0)
90 119 7 299 133
(41.7) (55.1) (3.2) (69.2) (30.8)
1.00 1.76 1.31 1.00 1.41
(Ref) (1.22–2.54) (0.47–3.65) (Ref) (1.06–1.87)
162 101 12 425 125
(58.9) (36.7) (4.4) (77.3) (22.7)
138 66 12 342 90
(63.9) (30.6) (5.6) (79.2) (20.8)
1.00 0.77 1.17 1.00 0.90
(Ref) (0.52–1.13) (0.51–2.70) (Ref) (0.66–1.22)
CI, 95% confidence interval; OR, odds ratio.
p-Value
0.25 0.38 0.18 0.002 0.60 0.017 0.18 0.71 0.48
ASSOCIATION BETWEEN IL-16 POLYMORPHISM AND 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 a (TNF-a), and transforming growth factor b (Chi et al., 2012). IL-6 and TNF-a 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 IL16 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 IL16 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 naso-
713
pharyngeal 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. Author Disclosure Statement
No competing financial interests exist. References
Azimzadeh P, Romani S, Mohebbi SR, et al. (2011) Interleukin16 (IL-16) gene polymorphisms in Iranian patients with colorectal cancer. J Gastrointestin Liver Dis 20:371–376. Azimzadeh P, Romani S, Mohebbi SR, et al. (2012) Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population. Cancer Genet 205:501–507. Balgkouranidou I, Karayiannakis A, Matthaios D, et al. (2013) Assessment of SOX17 DNA methylation in cell free DNA from patients with operable gastric cancer. Association with prognostic variables and survival. Clin Chem Lab Med 51: 1505–1510. Batai K, Shah E, Murphy AB, et al. (2012) Fine-mapping of IL16 gene and prostate cancer risk in African Americans. Cancer Epidemiol Biomarkers Prev 21:2059–2068. Blaschke V, Reich K, Middel P, et al. (1999) Expression of the CD4 + cell-specific chemoattractant interleukin-16 in mycosis fungoides. J Invest Dermatol 113:658–663. Burkart KM, Barton SJ, Holloway JW, et al. (2006) Association of asthma with a functional promoter polymorphism in the IL16 gene. J Allergy Clin Immunol 117:86–91. Center DM, Cruikshank W (1982) Modulation of lymphocyte migration by human lymphokines. I. Identification and characterization of chemoattractant activity for lymphocytes from mitogen-stimulated mononuclear cells. J Immunol 128:2563– 2568. Center DM, Kornfeld H, Cruikshank WW (1996) Interleukin 16 and its function as a CD4 ligand. Immunol Today 17:476–481. Chi J, Gu B, Zhang C, et al. (2012) Human herpesvirus 6 latent infection in patients with glioma. J Infect Dis 206:1394–1398. Cruikshank WW, Center DM, Nisar N, et al. (1994) Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression. Proc Natl Acad Sci U S A 91:5109–5113. Gao LB, Liang WB, Xue H, et al. (2009a). Genetic polymorphism of interleukin-16 and risk of nasopharyngeal carcinoma. Clin Chim Acta 409:132–135. Gao LB, Rao L, Wang YY, et al. (2009b). The association of interleukin-16 polymorphisms with IL-16 serum levels and risk of colorectal and gastric cancer. Carcinogenesis 30:295–299. Guo LH, Mittelbronn M, Brabeck C, et al. (2004) Expression of interleukin-16 by microglial cells in inflammatory,
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autoimmune, and degenerative lesions of the rat brain. J Neuroimmunol 146:39–45. Jemal A, Bray F, Center MM, et al. (2011) Global cancer statistics. CA Cancer J Clin 61:69–90. Koike M, Sekigawa I, Okada M, et al. (2002) Relationship between CD4( + )/CD8( + ) T cell ratio and T cell activation in multiple myeloma: reference to IL-16. Leuk Res 26:705–711. Kovacs E (2001) The serum levels of IL-12 and IL-16 in cancer patients. Relation to the tumour stage and previous therapy. Biomed Pharmacother 55:111–116. Li S, Deng Y, Chen ZP, et al. (2011) Genetic polymorphism of interleukin-16 influences susceptibility to HBV-related hepatocellular carcinoma in a Chinese population. Infect Genet Evol 11:2083–2088. Liebrich M, Guo LH, Schluesener HJ, et al. (2007) Expression of interleukin-16 by tumor-associated macrophages/activated microglia in high-grade astrocytic brain tumors. Arch Immunol Ther Exp (Warsz) 55:41–47. Louis DN, Ohgaki H, Wiestler OD, et al. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109. Lu H, Ouyang W, Huang C (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4:221–233. Mittelbronn M, Dietz K, Schluesener HJ, et al. (2001) Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol 101:249–255. Moss SF, Blaser MJ (2005) Mechanisms of disease: inflammation and the origins of cancer. Nat Clin Pract Oncol 2:90– 97; quiz 1 p following 113. Nakayama EE, Wasi C, Ajisawa A, et al. (2000) A new polymorphism in the promoter region of the human interleukin-16 (IL-16) gene. Genes Immun 1:293–294. Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109:93–108.
LUO ET AL.
Ostrom QT, Barnholtz-Sloan JS (2011) Current state of our knowledge on brain tumor epidemiology. Curr Neurol Neurosci Rep 11:329–335. Qin X, Peng Q, Lao X, et al. (2013) The association of interleukin-16 gene polymorphisms with IL-16 serum levels and risk of nasopharyngeal carcinoma in a Chinese population. Tumour Biol 35:1917–1924. Schwab JM, Schluesener HJ, Seid K, et al. (2001) IL-16 is differentially expressed in the developing human fetal brain by microglial cells in zones of neuropoesis. Int J Dev Neurosci 19:93–100. Van Meir EG, Hadjipanayis CG, Norden AD, et al. (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193. Wang DC, Zhang Y, Chen HY, et al. (2012) Hyperthermia promotes apoptosis and suppresses invasion in C6 rat glioma cells. Asian Pac J Cancer Prev 13:3239–3245. Zhang T, Wang H (2013) Variants of interleukin-16 associated with gastric cancer risk. Asian Pac J Cancer Prev 14: 5269–5273. Zhu J, Qin C, Yan F, et al. (2010) IL-16 polymorphism and risk of renal cell carcinoma: association in a Chinese population. Int J Urol 17:700–707.
Address correspondence to: Hai-Neng Huang, MD Department of Neurosurgery Affiliated Hospital of Youjiang Medical College for Nationalities Guangxi Baise 533000 People’s Republic of China E-mail: [email protected]
SHORT REPORT
Interleukin-16 Polymorphism Is Associated with an Increased Risk of Glioma Qi-Sheng Luo,1,* Jun-Li Wang,2,* Yuan-Yang Deng,1 Hua-Dong Huang,1 Huang-De Fu,1 Chuan-Yu Li,1 and Hai-Neng Huang1
Objective: Previous studies have shown that interleukin (IL)-16 is overexpressed in human and rat gliomas. Potential links between IL-16 polymorphisms and glioma risk are currently unclear. The aim of this study was to investigate the association between IL-16 polymorphisms and glioma risk. Methods: We examined IL-16 gene polymorphisms (i.e., rs4778889, rs11556218, and rs4072111) in 216 patients with glioma and 275 controls in a Chinese population. Genotypes were determined using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were used to evaluate the effect of the IL-16 polymorphisms on glioma risk. Results: 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. Conclusion: These findings suggest that the IL-16 rs11556218 polymorphism may be used as a susceptibility marker for glioma.
Introduction
G
lioma 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.
1 Department of Neurosurgery and 2Center of Clinical Laboratory, Affiliated Hospital of Youjiang Medical College for Nationalities, Guangxi, Baise, People’s Republic of China. *These authors contributed equally to this work.
711
712
LUO ET AL. Genotyping
Table 1. Characteristics of Study Subjects Controls, n = 275
Variables
Age (years) 44.4 – 12.5 Gender (%) Male 155 (56.4) Female 120 (43.6) WHO grade (%) I-II — III-IV —
Patients with glioma, n = 216
p-Value
45.0 – 16.1
NS
123 (56.9) 93 (43.1)
NS
120 (55.6) 96 (44.4)
Genomic DNA was extracted from peripheral blood samples with an extraction kit (Qiagen, Chastworth, CA). IL-16 polymorphism genotyping was performed using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. Primers for amplification and restriction enzymes were described previously (Gao et al., 2009b). Statistical analyses
NS, no significance.
Materials and Methods Study population
The hospital-based case–control study was conducted in the hospital. A total of 491 subjects, including 275 controls and 216 patients with gliomas were recruited in this study between June 2010 and July 2013. Histological diagnosis and grading of tumors were performed according to the World Health Organization standards (Louis et al., 2007). The patients with a self-reported history of cancer were excluded. Control subjects were randomly selected from the general health check-up division of the hospital during the same time period. We excluded those participants who had central nervous system-related diseases or a history of cancer. The mean age – standard deviation was 44.4 – 12.5 in controls and 45.0 – 16.1 in cases, respectively. All cases and controls enrolled in this study were genetically unrelated Han Chinese from Baise and its surrounding regions. There was no difference according to age, gender, and living area between cases and controls. The approval to conduct this study was granted by the ethics committee of the hospital, and written informed consent was provided by all subjects.
All statistical analyses were performed using the Statistical Package for the Social Sciences software version 13.0 (SPSS, Chicago, IL). The chi-square and Student’s t-tests were used to test differences of sociodemographic factors between cases and controls. Genotypic distributions in controls for each SNP were tested for departure from the Hardy–Weinberg equilibrium (HWE) using the chi-square test. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were used to evaluate the effect of the IL-16 polymorphisms on glioma risk. A p value < 0.05 was considered statistically significant. 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.
Table 2. Genotype Distributions of IL-16 Polymorphisms Between Cases and Controls Polymorphisms rs4778889 T/C TT CT CC T allele C allele rs11556218 T/G TT TG GG T allele G allele rs4072111 C/T CC CT TT C allele T allele
Controls, n = 275 (%)
Gliomas, n = 216 (%)
OR (95% CI)
165 99 11 429 121
(60.0) (36.0) (4.0) (78.0) (22.0)
142 68 6 352 80
(65.7) (31.5) (2.8) (81.5) (18.5)
1.00 0.80 0.63 1.00 0.81
(Ref) (0.55–1.17) (0.23–1.76) (Ref) (0.59–1.11)
152 114 9 418 132
(55.3) (41.5) (3.3) (76.0) (24.0)
90 119 7 299 133
(41.7) (55.1) (3.2) (69.2) (30.8)
1.00 1.76 1.31 1.00 1.41
(Ref) (1.22–2.54) (0.47–3.65) (Ref) (1.06–1.87)
162 101 12 425 125
(58.9) (36.7) (4.4) (77.3) (22.7)
138 66 12 342 90
(63.9) (30.6) (5.6) (79.2) (20.8)
1.00 0.77 1.17 1.00 0.90
(Ref) (0.52–1.13) (0.51–2.70) (Ref) (0.66–1.22)
CI, 95% confidence interval; OR, odds ratio.
p-Value
0.25 0.38 0.18 0.002 0.60 0.017 0.18 0.71 0.48
ASSOCIATION BETWEEN IL-16 POLYMORPHISM AND 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 a (TNF-a), and transforming growth factor b (Chi et al., 2012). IL-6 and TNF-a 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 IL16 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 IL16 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 naso-
713
pharyngeal 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. Author Disclosure Statement
No competing financial interests exist. References
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Address correspondence to: Hai-Neng Huang, MD Department of Neurosurgery Affiliated Hospital of Youjiang Medical College for Nationalities Guangxi Baise 533000 People’s Republic of China E-mail: [email protected]
