Abstract
We conducted a case-control study to assess the role of IL-16 rs4778889, rs11556218 and rs8034928 polymorphisms in the development of RCC. This case-control study included 181 patients with RCC and 278 control patients. The genotyping of IL-16 rs4778889, rs11556218 and rs8034928 polymorphisms were performed using polymerase chain reaction (PCR) combined with restriction fragment length polymorphism analysis. By χ2 test, we found that patients with RCC were more likely to suffer from hypertension (χ2 = 9.06, P = 0.003) and diabetes (χ2 = 7.91, P = 0.005). By unconditional logistic regression analysis, the CC genotype of rs4778889 was associated with an increased risk of RCC compared to TT genotype, and the adjusted OR (95% CI) was 3.58 (1.59-8.31). In dominant model and recessive model, we found the rs4778889 polymorphisms were associated with an elevated increased risk of RCC, and the adjusted ORs (95% CI) were 1.64 (1.10-2.43) and 3.07 (1.40-6.98), respectively. We found that rs4778889 polymorphism had interaction with hypertension (OR = 2.44, 95% CI = 1.01-6.00) and diabetes (OR = 6.91, 95% CI = 1.44-37.05) in the risk of RCC. In conclusion, the results of our study suggested an association between the IL-16 rs4778889 polymorphism and an elevated risk of RCC.
Keywords: Interleukin-16, polymorphism, renal cell cancer
Introduction
Renal cell cancer (RCC) is a complex-trait disease, and is the ninth most common tumor in men and the fourteenth most common tumor in women [1]. The incidence of RCC is increasing steadily, and it increased by 2% and 3% per year in developed countries [1]. In the Chinese population, there were 44,375 new cases with RCC per 10,000 people [2]. The process of RCC is involved in many complex factors, such as hypertension, cigarette smoking, alcohol drinking, occupational exposures to chemicals and family history of RCC [3-6]. However, not all patients who exposed to the risk factors of RCC would develop RCC, which suggests that genetic factors may contribute to the development of this cancer.
An increasing amount of evidence has reported that the inflammation contributes to the pathogenesis of RCC [7-10], and that several cytokines are associated with the arterial wall inflammatory process. Variations in genes related to the inflammatory system may alter the pattern of proinflammatory cytokine production, and thus the development of RCC, affecting predisposition and prevalence [9,10].
Interleukin-16 (IL-16) is a cytokine with many important functions, and is involved in several contradictory processes. It plays key roles in activating CD4+ T cells, macrophages, monocytes, eosinophils, and dendritic cells [11]. IL-16 is reported to be involved in promoting the secretion of tumor-associated inflammatory cytokines which contribute to the process of tumorigenesis, such as tumor necrosis factor-α, IL-1β, IL-6 and IL-15 [12-14]. Only one previous study reported the association between IL-16 gene polymorphisms and development and RCC (Zhu et al., 2010). Three functional polymorphisms in the IL-16 gene rs4778889, rs11556218 and rs8034928 are found to be correlated with inflammatory diseases [15,16]. We conducted a case-control study to assess the role of IL-16 rs4778889, rs11556218 and rs8034928 polymorphisms in the development of RCC.
Material and methods
Subjects
This case-control study included 181 patients with RCC and 278 control patients. All the RCC patients were enrolled in our hospital between February 2013 and December 2014, and patients with RCC were newly diagnosed and confirmed by pathological tissue. Patients who had primary tumors other than RCC, tumors of an unknown origin or any histopathological diagnosis other than RCC were excluded.
Cancer free control subjects were randomly enrolled from individuals seeking for health check-up in our hospital during the same period time.
The demographic and clinical characteristics of patients with RCC were collected from a self-designed questionnaire. The demographic data included age, gender, cigarette smoking, cigarette smoking, alcohol drinking, hypertension, diabetes and family history of cancer. The clinical data included TNM stage and histology. The TNM stage was determined by pathologists based on the American Joint Committee on Cancer TNM classification.
Written informed consents were obtained from patients with RCC and control subjects prior to enrolling into our study. This work was approved by the Institute Research Ethics Committee of our hospital.
Genotyping
Five mL peripheral venous blood sample was collected from each patient with RCC and control subject after enrollment into this study. The blood samples were stored at -20°C until use. Genomic DNA was isolated from peripheral blood lymphocytes using Qiagen blood mini kit (Qiagen, Germany) based on the manufacturer’s protocol. The genotyping of IL-16 rs4778889, rs11556218 and rs8034928 polymorphisms were performed using polymerase chain reaction (PCR) combined with restriction fragment length polymorphism analysis. The forward and reverse primers used to amplify IL-16 rs4778889 were 5’-CAATGCCAGTCCCTCCACA-3’ and 5’-AGGTCATGGGCTCATACTG-3’, respectively; the forward and reverse primers for IL-16 rs11556218 were 5’-CTGGTCCTGACTTCCTTTGG-3’ and 5’-TGGTGCGTGGTCCCCTTG-3’, respectively; the forward and reverse primers for IL-16 rs8034928 were 5’-CCTTATTTGAAGAGAGC-3’ and 5’-TGCAGATTTCCCAGGTTC-3’, respectively. For PCR amplification, amplification was performed as follows: 95°C for 5 min, 30 cycles of 95°C for 30s, 63°C for 30 s, and 72°C for 30 s and a final extension step of 72°C for 10 min. The product sizes for IL-16 rs4778889, rs11556218 and rs8034928 were 90 bp, 136 bp and 171 bp, respectively.
Statistical analysis
The demographic and clinical data of patients with RCC and control subjects were shown as mean ± standard deviation and frequency (percentage) of study subjects. The demographic and clinical data between patients with RCC and control subjects were compared by t-test or χ2-test. Hardy-Weinberg equilibrium of genetic distributions in controls was tested with a goodness of fit χ2 test with one degree of freedom, which was used to compare the observed genotype frequencies in the subjects with the expected genotype frequencies. Unconditional logistic regression was used to assess the IL-16 rs4778889, rs11556218 and rs8034928 polymorphisms and the risk of RCC, and the results were expressed by odds ratios (OR) and its 95% confidence intervals (95% CI). A P-value less than 0.05 were considered statistically significant. Statistical analysis was done using statistical package SPSS 16.0 software (SPSS, Chicago, IL, USA).
Results
The baseline characteristics of patients with RCC and control subjects were described in Table 1. By χ2 test, we found that patients with RCC were more likely to suffer from hypertension (χ2 = 9.06, P = 0.003) and diabetes (χ2 = 7.91, P = 0.005). However, no significant difference was found between patients with RCC and control subjects in terms of age (t = 7.91, P = 0.16), sex (χ2 = 0.17, P = 0.68), cigarette smoking (χ2 = 3.26, P = 0.07), alcohol drinking (χ2 = 0.24, P = 0.62) and family history of cancer (χ2 = 0.81, P = 0.37). Of 181 patients with RCC, 113 (62.43%) at I-II TNM stage, 68 (37.57%) at III-IV TNM stage, and 147 (81.22%) were clear cell RCC.
Table 1.
Demographic and clinical characteristics of patients with RCC and control subjects
| Characteristics | Cases | % | Controls | % | t or χ2 test | P value |
|---|---|---|---|---|---|---|
| Age, years | 54.65±9.34 | 53.76±9.10 | 1.01 | 0.16 | ||
| Sex | ||||||
| Male | 119 | 65.75 | 188 | 67.63 | ||
| Female | 62 | 34.25 | 90 | 32.37 | 0.17 | 0.68 |
| Cigarette smoking | ||||||
| Never | 102 | 56.35 | 180 | 64.75 | ||
| Ever | 79 | 43.65 | 98 | 35.25 | 3.26 | 0.07 |
| Alcohol drinking | ||||||
| Never | 96 | 53.04 | 154 | 55.40 | ||
| Ever | 85 | 46.96 | 124 | 44.60 | 0.24 | 0.62 |
| Hypertension | ||||||
| No | 129 | 71.27 | 231 | 83.09 | ||
| Yes | 52 | 28.73 | 47 | 16.91 | 9.06 | 0.003 |
| Diabetes | ||||||
| No | 156 | 86.19 | 261 | 93.88 | ||
| Yes | 25 | 13.81 | 17 | 6.12 | 7.81 | 0.005 |
| Family history of cancer | ||||||
| Never | 169 | 93.37 | 265 | 95.32 | ||
| Ever | 12 | 6.63 | 13 | 4.68 | 0.81 | 0.37 |
| Stage | ||||||
| I-II | 113 | 62.43 | ||||
| III-IV | 68 | 37.57 | ||||
| Histology | ||||||
| Clear cell | 147 | 81.22 | ||||
| Papillary | 8 | 4.42 | ||||
| Chromophobe | 17 | 9.39 | ||||
| Others | 9 | 4.97 | ||||
By χ2 test with one degree of freedom, we found the genotype frequencies of IL-16 rs4778889, rs11556218 and rs8034928 did not deviate from HWE, and the P values (for HWE) were 0.34, 0.22 and 0.45, respectively (Table 2). We found significant differences in the genotype frequencies of rs4778889 (χ2 = 12.75, P = 0.002); however, rs11556218 and rs8034928 exhibited no such differences. By unconditional logistic regression analysis, we found that the CC genotype of rs4778889 was associated with an increased risk of RCC compared to TT genotype, and the adjusted OR (95% CI) was 3.58 (1.59-8.31). In dominant model and recessive model, we found the rs4778889 polymorphisms were associated with an elevated increased risk of RCC, and the adjusted ORs (95% CI) were 1.64 (1.10-2.43) and 3.07 (1.40-6.98), respectively.
Table 2.
Genotype frequencies of IL-16 rs4778889, rs11556218 and rs8034928 among the cases with RCC and controls and their association with risk of RCC
| Genotypes | Patients | % | Controls | % | χ2 test | P value | HWE | OR (95% CI)1 | P value |
|---|---|---|---|---|---|---|---|---|---|
| rs4778889 | |||||||||
| Codminant | |||||||||
| TT | 82 | 45.30 | 160 | 57.55 | 1.0 (Ref.) | - | |||
| TC | 77 | 42.54 | 106 | 38.13 | 1.42 (0.93-2.15) | 0.08 | |||
| CC | 22 | 12.15 | 12 | 4.32 | 12.75 | 0.002 | 0.28 | 3.58 (1.59-8.31) | <0.001 |
| Dominant | |||||||||
| TT | 82 | 45.30 | 160 | 57.50 | 1.0 (Ref.) | - | |||
| TC+CC | 99 | 54.70 | 118 | 42.45 | 6.6 | 0.01 | 1.64 (1.10-2.43) | 0.01 | |
| Recessive | |||||||||
| TT+TC | 159 | 87.85 | 266 | 95.68 | 1.0 (Ref.) | - | |||
| CC | 22 | 12.15 | 12 | 4.32 | 9.82 | 0.002 | 3.07 (1.40-6.98) | 0.002 | |
| rs11556218 | |||||||||
| Codminant | |||||||||
| TT | 94 | 51.93 | 155 | 55.76 | 1.0 (Ref.) | - | |||
| TG | 75 | 41.44 | 108 | 38.85 | 1.15 (0.76-1.72) | 0.5 | |||
| GG | 12 | 6.63 | 15 | 5.40 | 0.76 | 0.68 | 0.49 | 1.32 (0.54-3.16) | 0.5 |
| Dominant | |||||||||
| TT | 94 | 51.60 | 155 | 55.70 | 1.0 (Ref.) | - | |||
| TG+GG | 87 | 48.07 | 123 | 44.24 | 0.65 | 0.42 | 1.17 (0.79-1.73) | 0.42 | |
| Recessive | |||||||||
| TT+TG | 169 | 93.37 | 263 | 94.60 | 1.0 (Ref.) | - | |||
| GG | 12 | 6.63 | 15 | 5.40 | 0.3 | 0.58 | 1.24 (0.52-2.93) | 0.58 | |
| rs8034928 | |||||||||
| Codminant | |||||||||
| TT | 95 | 52.49 | 154 | 55.40 | 1.0 (Ref.) | - | |||
| TC | 73 | 40.33 | 109 | 39.21 | 1.09 (0.72-1.64) | 0.68 | |||
| CC | 13 | 7.18 | 15 | 5.40 | 0.78 | 0.68 | 0.45 | 1.40 (0.59-3.32) | 0.39 |
| Dominant | |||||||||
| TT | 95 | 52.49 | 154 | 55.40 | 1.0 (Ref.) | - | |||
| TC+CC | 86 | 47.51 | 124 | 44.60 | 0.37 | 0.54 | 1.12 (0.76-1.67) | 0.54 | |
| Recessive | |||||||||
| TT+TC | 168 | 92.82 | 263 | 94.60 | 1.0 (Ref.) | - | |||
| CC | 13 | 7.18 | 15 | 5.40 | 0.61 | 0.43 | 1.36 (0.58-3.14) | 0.43 |
Adjusted for sex, age, hypertension and diabetes.
Moreover, we conducted stratification analysis between rs4778889 and risk of RCC by cigarette smoking, alcohol drinking, hypertension and diabetes (Table 3). We found that rs4778889 polymorphism was associated with development of RCC regardless of cigarette smoking and alcohol drinking, but this SNP had interaction with hypertension (OR = 2.44, 95% CI = 1.01-6.00) and diabetes (OR = 6.91, 95% CI = 1.44-37.05) in the risk of RCC.
Table 3.
Stratification analysis between IL16 rs4778889 and risk of RCC by cigarette smoking, alcohol drinking, hypertension and diabetes
| Variables | Patients | Controls | OR (95% CI) | P value | ||
|---|---|---|---|---|---|---|
|
| ||||||
| TT | TC+CC | TT | TC+CC | |||
| Cigarette smoking | 82 | 99 | 160 | 118 | ||
| Never | 48 | 54 | 104 | 76 | 1.54 (0.92-2.58) | 0.08 |
| Ever | 34 | 45 | 56 | 42 | 1.76 (0.93-3.36) | 0.06 |
| Alcohol drinking | ||||||
| Never | 44 | 52 | 88 | 66 | 1.58 (0.91-2.72) | 0.08 |
| Ever | 38 | 47 | 72 | 52 | 1.71 (0.95-3.11) | 0.06 |
| Hypertension | ||||||
| No | 59 | 70 | 129 | 102 | 1.50 (0.95-2.37) | 0.07 |
| Yes | 23 | 29 | 31 | 16 | 2.44 (1.01-6.00) | 0.03 |
| Diabetes | ||||||
| No | 74 | 82 | 147 | 114 | 1.43 (0.94-2.17) | 0.08 |
| Yes | 8 | 17 | 13 | 4 | 6.91 (1.44-37.05) | 0.005 |
Discussion
In the present study, we investigated whether the three functional SNPs in IL-16 rs4778889, rs11556218 and rs8034928 could influence the susceptibility to RCC in a Chinese population. We found that the CC genotype of rs4778889 was associated with an increased risk of RCC compared to TT genotype, and we revealed the IL-16 rs4778889 polymorphisms were associated with an elevated increased risk of RCC in dominant model and recessive models, especially in patients with hypertension or diabetes. Therefore, our results suggest that IL-16 rs4778889 polymorphism may play an important role in the development of RCC, and this gene could be used as a genetic marker for identification the development of RCC in a Chinese population.
IL-16 is a multifunctional cytokine and plays a critical role in inflammatory diseases and tumor growth as well as tumor procession. Previous studies have reported that IL-16 gene polymorphisms are association with the development of various cancers, such as colorectal cancer, gastric cancer, nasopharyngeal carcinoma, hepatocellular carcinoma and glioma [17-21]. Gao et al. conducted a case-control study with 376 colorectal cancer patients and 220 gastric cancer patients in a Chinese population, and they found that the rs11556218 polymorphism was significantly associated with the susceptibility to colorectal cancer and gastric cancer patients [17]. In human nasophargyngeal carcinoma, Gao et al. conduced another study in a Chinese population with 206 nasopharyngeal cancer patients, and they reported that rs11556218 polymorphism contributes to the susceptibility to nasopharyngeal cancer [18]. Li et al. analyzed the association between three SNPs of IL-16 polymorphisms and development of HBV-related hepatocellular carcinoma, and they found that rs11556218 and rs4072111 were associated with susceptibility to chronic HBV infection and risk of hepatocellular carcinoma [19]. Azimzadeh et al. reported that IL-16 rs11556218 and rs4778889 polymorphisms could influence the development of colorectal cancer [20]. Qin et al. reported that IL-16 rs11556218 polymorphism was correlated with an elevated risk of nasopharyngeal carcinoma [21]. A recent meta-analysis reported that the IL-16 rs11556218 polymorphism was significantly correlated with elevated cancer risk in Asian population [22]. The above-mentioned studies suggest that IL-16 gene polymorphisms are associated with development of cancers.
Our study found that IL-16 rs4778889 polymorphism played a major role in susceptibility to RCC. A possible mechanism for IL-16 rs4778889 polymorphism in modulating the development of RCC is that the IL-16 rs4778889 polymorphism regulates the expression of serum levels of IL-16, and the over-expressed IL-16 is associated with the development of tumorigenesis of RCC. Only one previous study has reported that IL-16 -295 T>C polymorphism is significantly associated with development of RCC [23]. However, no studies reported the association between IL16 rs4778889, rs11556218 and rs8034928 and development of RCC. Moreover, our study found that the rs4778889 polymorphism had interaction with hypertension and diabetes in the risk of RCC. Previous studies have reported that IL-16 expression was association with development of type 2 diabetes mellitus and hypertension related diseases [24,25]. Further studies with large sample sizes are greatly required to confirm our study.
Two limitations in our study should be taken into consideration. First, patients with RCC and control subjects were selected from only one hospital, which would cause selection bias in our study. However, the genotype distributions of IL-16 rs4778889, rs11556218 and rs8034928 confirm with the Hardy-Weinberg equilibrium in controls, which suggests that our population may represent the general population. Second, the sample size of our study is relatively small, which could reduce the statistical power to find differences between groups. Therefore, further studies with participants from multiple locations and a larger sample size are required to confirm our results.
In conclusion, the results of our study suggested an association between the IL-16 polymorphisms and an elevated risk of RCC, especially in patients with diabetes mellitus and hypertension. Our study offers insights into the influence of IL-16 on development of RCC.
Disclosure of conflict of interest
None.
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