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Research Article

Role of IL17A rs2275913 and rs3748067 polymorphisms in the risk cervical cancer

Received: May 19, 2017
Accepted: August 31, 2017
Published: December 02, 2016
Genet.Mol.Res. 16(3): gmr16038826
DOI: 10.4238/gmr16038826

Abstract

Cervical cancer is a serious public health problem and is associated with high cancer-related mortality in females worldwide. The expression of IL17A can increase the migration and invasiveness of cervical cancer cells by activating the NF-κB signal pathway. Single-nucleotide polymorphisms (SNPs) can alter gene function and protein expression. We examined the association between two IL17A SNPs (rs2275913 and rs3748067) and the risk of cervical cancer. We also investigated the interaction between IL17A -174G/C and -572C/G mutations and environmental factors. Our 1:2 matched case-control study included 185 cervical cancer patients and 370 healthy controls. The IL17A rs2275913 and rs3748067 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Using logistic regression analysis, we found that individuals harboring the TT genotype of IL17A rs3748067 had an increased risk of cervical cancer compared with those carrying the CC genotype, and the adjusted OR (95%CI) was 6.29 (2.30-19.81). Moreover, individuals carrying the T allele of IL17A rs3748067 were more susceptible to cervical cancer than those with the C allele, and the adjusted OR (95%CI) was 2.31 (1.53-3.50). No significant interaction was observed between the IL17A rs2275913 polymorphism and cervical cancer risk. In conclusion, our study suggests that the IL17A rs3748067 polymorphism is independently associated with the risk of cervical cancer, and has a relationship with human papillomavirus infection with regard to the risk of cervical cancer.

Introduction

Cervical cancer is a serious public health problem and is associated with high cancer-related mortality in females worldwide, including China (IARC, 2012). Cervical cancer is the seventh leading cause of cancer-related deaths in women in China, and there were approximately 62,000 new cervical cancer cases and 30,000 deaths in 2012 (IARC, 2012). It is well known that the etiology of cervical cancer involves multiple factors such as persistent infection with oncogenic human papillomavirus (HPV) and chronic inflammation, and long-term use of oral contraceptives, as well as multiple sexual partners (Rajeevan et al., 2005; Villa, 2006; Ribeiro, 2008; Jemal et al., 2011; Bedoya et al., 2013). It is believed that such factors enhance carcinogenesis and promote immunosuppression, which in turn increases the inflammation associated with cervical cancer. Recently, many studies have indicated that tumor angiogenesis in cervical cancer is influenced by many growth factors and various cytokines such as vascular endothelial growth factor, chemokines, tumor necrosis factor-a, and various interleukins (IL6, IL2, IL4, IL10, IL17, and IL27) (Saijo et al., 2015; Yin et al., 2015; Akhavan et al., 2016; Sun et al., 2016; Wang et al., 2016).

IL17A is a pro-inflammatory cytokine; its role is crucial in the inhibition of apoptosis, the stimulation of cellular proliferation and angiogenesis, and the promotion of invasive cancers with metastatic potential (Ji and Zhang, 2010; Ngiow et al., 2010). The authors of previous studies have reported that the expression of IL17A can increase the migration and invasiveness of cervical cancer cells by activating the p38/NF-kB signal pathway (Feng et al., 2014). It has also been reported that IL17A can promote the growth of tumors by stimulating angiogenesis and invasiveness, and by inhibiting apoptosis (Benchetrit et al., 2002). Previous studies have indicated that high expression of IL17A is correlated with the development and progression of tumors, and the IL17A gene is regulated at the transcriptional level (Chen et al., 2016; Mohammadi et al., 2016; Parajuli et al., 2016). Moreover, single nucleotide polymorphisms (SNPs) can alter gene function and protein expression. To date, four research groups have investigated the association between IL17A gene polymorphisms and the risk of cervical cancer, but the results are conflicting (Cong et al., 2015; Li et al., 2015a; Lv et al., 2015; Sun et al., 2015). Moreover, the authors of previous studies did not investigate the interaction between IL17A polymorphisms and environmental factors with regard to the risk of cervical cancer. In the present study, we examined the association between two IL17A SNPs (rs2275913 and rs3748067) and the risk of cervical cancer. We also investigated the interaction between IL17A -174G/C and -572C/G mutations and environmental factors.

Materials and Methods

Subjects

We conducted a 1:2 matched case-control study that included 185 cervical cancer patients and 370 healthy controls. These patients were recruited from the Department of Gynecology of the First People’s Hospital of Shangqiu between March 2013 and March 2015. All the cervical cancer patients underwent surgery in our hospital and all cases were confirmed by histopathologic examination. Patients with cervical cancer were excluded from the study if they had received chemotherapy or radiotherapy treatment before participation. Patients with a history of secondary or recurrent malignant tumors, end-stage renal or liver disease, or malnutrition were also excluded.

During the period mentioned above, a total of 370 individuals were recruited from the outpatients clinics and physical examination centers of the First People’s Hospital of Shangqiu. All the controls were pronounced free of malignant tumors, gynecological diseases, end-stage renal or liver disease, or malnutrition.

Details of potential cervical cancer risk factors were obtained using an ad hoc questionnaire or from medical records; they included age, number of sexual partners, menopausal status, oral contraceptive use, family history of cancer, HPV status, International Federation of Gynecology and Obstetrics (FIGO) stage, and histology.

Genotyping of IL17A rs2275913 and rs3748067

Peripheral blood samples were collected from all subjects in 0.129 M ethylenediaminetetraacetic acid-containing tubes, and were subjected to genomic DNA extraction using a DNA extraction kit (TaKaRa Bio, Dalian, China) according to manufacturer instructions. The genotyping of the IL17A rs2275913 and rs3748067 SNPs was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using a PCR Thermocycle Instrument (MJ Research Inc., St. Bruno, Canada). The primers were provided by ABI Applied Biosystems (Waltham, MA, USA). The forward and reverse primers for IL17A rs2275913 were 5'-ACTTCGTGCATGACTTCAGC-3' and 5'-CTGATTGGAAACCTTATTAAG-3', respectively. The forward and reverse primers for IL17A rs3748067 were 5'-GGAGACGCCTTGAAGTAACTGC-3' and 5'-GAGTTTCCTCTGACTCCATCGCAG-3', respectively. The PCR for genotyping IL17A rs2275913 and rs3748067 was carried out in a 50- mL reaction mixture comprising 20 pmol each primer, 4 ng (2 mL) DNA, 1.25 mmol dNTP mix (4 mL), 2.0 mM MgCl2 (25 mM), 1.25 U Taq polymerase (0.25 mL), and 5 mL 10X PCR Buffer Tango and ddH2O (ABI Applied Biosystems Inc.). The PCR regimen for IL17A rs2275913 was as follows: initiation at 94°C for 5 min; 35 cycles of 94°C for 30 s, 57°C for 60 s, and 72°C for 60 s; and a final cycle of 72°C for 10 min. The PCR regimen for IL17A rs3748067 was as follows: 95°C for 5 min; 35 cycles of 94°C for 30 s, 60°C for 60 s, and 72°C for 60 s; and a final cycle of 72°C for 6 min. The conditions for restriction digestion included 2 mL 10X buffer R, 10 mL PCR products, 1 mL restriction enzyme, and 18 mL ddH2O. The restriction enzymes (10 U/mL) for IL17A rs2275913 and rs3748067 were XmnI and ApoI, respectively. The PCR amplification and enzyme digestion products of IL17A rs2275913 and rs3748067 were observed on 1.5% agarose gel and presented in ultraviolet light.

Statistical analysis

The differences in potential cervical cancer risk factors between patients with cervical cancer and controls were compared using the Pearson chi-square (χ2) test or the Student t-test. Deviation of the genotype frequencies of IL17A rs2275913 and rs3748067 from the Hardy Weinberg equilibrium was analyzed using the Pearson chi-square test. The role of IL17A rs2275913 and rs3748067 SNPs in cervical cancer risk was evaluated using logistic regression analysis; odds ratios (ORs) and 95% confidence intervals (95%CIs) were taken to estimate the relationship. All P values were two-sided, and P values less than 0.05 were considered statistically significant. All data analyses were performed using SPSS Statistics for Windows, Version 17.0 (SPSS Inc., Chicago, IL, USA).

Results

The restriction products of IL17A rs2275913 and rs3748067 were 246 and 230 bp in size, respectively. For the IL17A rs2275913 SNP, the restriction fragment lengths were 246 and 122 bp for the GG genotype, 368, 246, and 122 bp for the GA genotype, and 368 bp for the AA genotype. For the IL17A rs3748067 SNP, the fragment lengths were 230 and 128 bp for the TT genotype, 358, 230, and 128 bp for the CT genotype, and 358 bp for the CC genotype.

General information about the cervical cancer patients and the controls is presented in Table 1. The Pearson chi-square test revealed that cervical cancer patients had more sexual partners (χ2 = 16.31, P < 0.001), were more likely to have a family history of cancer (χ2 = 11.79, P = 0.001), and were more likely to have HPV infection (χ2 = 336.10, P < 0.001) compared with the controls. However, no significant differences were found between cervical cancer patients and controls with respect to age (χ2 = 10.82, P = 0.37), menopausal status (χ2 = 1.41, P = 0.23), or oral contraceptive use (χ2 = 3.45, P = 0.06). Of the 185 cervical cancer patients, 122 (65.95%) were at stage I-II and 63 (34.05%) were at stage III-IV. The histological composition of the patients was as follows: 151 (81.62%) had squamous cell carcinoma, 30 (16.22%) had adenocarcinoma, and 4 (2.16%) had sarcoma.

Variables Patients (N = 185) % Controls (N = 370) % χ2 value P value
Age            
<50 79 42.70 173 46.76    
≥50 106 57.30 197 53.24 0.82 0.37
Sexual partners            
0 2 1.08 13 3.51    
1-3 99 53.51 250 67.57    
≥3 84 45.41 107 28.92 16.31 <0.001
Menopausal            
Pre-menopausal 60 32.43 139 37.57    
Post-menopausal 125 67.57 231 62.43 1.41 0.23
Oral contraceptive users            
No 23 12.43 69 18.65    
Yes 162 87.57 301 81.35 3.45 0.06
Family history of cancer            
No 154 83.24 343 92.70    
Yes 31 16.76 27 7.30 11.79 0.001
HPV infection            
No 0 0.00 304 82.16    
Yes 185 100.00 66 17.84 336.10 <0.001
FIGO stage            
I-II 122 65.95        
III-IV 63 34.05        
Histology            
Squamous cell carcinoma 151 81.62        
Adenocarcinoma 30 16.22        
Sarcoma 4 2.16        

Table 1. General information about the cervical cancer patients and the controls.

The distribution frequencies of IL17A rs2275913 and rs3748067 are shown in Table 2. The IL17A rs2275913 and rs3748067 minor allele frequencies in the controls were 0.2959 and 0.0730, respectively [similar to those available on the National Center of Biotechnology Information database (https://www.ncbi.nlm.nih.gov/snp/)]. There were significant differences in the genotype frequencies of IL17A rs3748067 between the cervical cancer patients and the controls (χ2 = 18.26, P < 0.001), whereas there were no such differences between the genotype frequencies of IL17A rs2275913 (χ2 = 0.77, P = 0.68). The chi-square test revealed that the genotype distributions of IL17A rs2275913 (χ2 = 21.52, P < 0.001) and rs3748067 (χ2 = 9.59, P = 0.002) did not agree with the Hardy-Weinberg equilibrium in the controls.

IL17A Patients (N = 185) % Controls (N = 370) % MA MAF in controls χ2 value P value χ2 for HWE P for HWE
rs2275913                    
GG 95 51.35 202 54.59            
GA 60 32.43 117 31.62            
AA 30 16.22 51 13.78 A 0.2959 0.77 0.68 21.52 <0.001
rs3748067                    
CC 145 78.38 322 87.03            
CT 23 12.43 42 11.35            
TT 17 9.19 6 1.62 T 0.0730 18.26 <0.001 9.59 0.002

Table 2. Distribution of IL17A rs2275913 and rs3748067 polymorphisms in the patients with cervical cancer and in the controls.

Using logistic regression analysis, we found that individuals harboring the TT genotype of IL17A rs3748067 had an increased risk of cervical cancer compared with those with the CC genotype, and the adjusted OR (95%CI) was 6.29 (2.30-19.81) (Table 3). Moreover, individuals carrying the T allele of IL17A rs3748067 had a higher risk of developing cervical cancer compared with those with the C allele, and the adjusted OR (95%CI) was 2.31 (1.53- 3.50). However, no significant relationship was detected between the IL17A rs2275913 SNP and cervical cancer risk.

IL17A Patients (N = 185) % Controls (N = 370) % OR (95%CI) P value
rs2275913            
GG 95 51.35 202 54.59 Reference -
GA 60 32.43 117 31.62 1.09 (0.72-1.65) 0.67
AA 30 16.22 51 13.78 1.25 (0.72-2.15) 0.39
Allele            
G 250 67.57 521 70.41 Reference -
A 120 32.43 219 29.59 1.14 (0.86-1.51) 0.33
rs3748067            
CC 145 78.38 322 87.03 Reference -
CT 23 12.43 42 11.35 1.22 (0.67-2.16) 0.48
TT 17 9.19 6 1.62 6.29 (2.30-19.81) <0.001
Allele            
C 313 84.59 686 92.71 Reference -
T 57 15.41 54 7.29 2.31 (1.53-3.50) <0.001

Table 3. Association between IL17A rs2275913 and rs3748067 polymorphisms and risk of cervical cancer.

We investigated the interaction between the IL17A rs3748067 polymorphism and environmental factors using Spearman correlation analysis and found that the IL17A rs3748067 SNP had a relationship with HPV infection (Spearman correlation coefficient = 0.142, P = 0.005) (Table 4). However, we did not find any relationship between the IL17A polymorphism and age, number of sexual partners, or family history of cancer with regard to the risk of cervical cancer (P > 0.05).

Variables   rs3748067
  Spearman correlation coefficient P value
Age 0.034 0.47
Sexual partner 0.025 0.66
Family history of cancer 0.047 0.31
HPV infection 0.142 0.005

Table 4. Interaction between the IL17A rs3748067 polymorphism and environmental factors with regard to the risk of cervical cancer.

Discussion

Inflammation-related cytokines are involved in altering epithelial tissues in many types of cancer (Sun et al., 2015; Wang et al., 2015; Yang et al., 2016). The inflammatory status of the human body can affect the acceleration of tumor progression, the reconstruction of tumor tissue, the promotion of angiogenesis, and the inhibition of the natural antitumor immune response (Chechlinska et al., 2010). In the current study, we found that the IL17A rs3748067 SNP was independently associated with the risk of cervical cancer, and a significant relationship was detected between the IL17A rs3748067 SNP and HPV infection with regard to the risk of cervical cancer (Sun et al., 2015; Wang et al., 2015; Yang et al., 2016).

IL17A is a special cytokine that is secreted by helper T cells; it recruits neutrophils that release inflammatory factors, and promotes cell proliferation, angiogenesis, and metastasis, resulting in the onset of chronic inflammation and tumors (Yang et al., 2014). Previous studies have indicated that high expression of IL17A is correlated with the development and progression of tumors, and IL17A is regulated at the transcriptional level (Chen et al., 2016; Mohammadi et al., 2016; Parajuli et al., 2016). Polymorphisms in cytokine factors can influence their function and expression, or cause abnormal cell proliferation, thereby triggering cell transformation and maintaining the autonomous proliferation of the transformed cells (Jia et al., 2015; Omrane et al. (2015)). Therefore, polymorphisms in IL17A could influence the expression of the IL17A protein, and thus influence an individual’s susceptibility to tumors.

The authors of previous studies have reported a relationship between IL17A polymorphisms and the risk of several kinds of cancer such as hepatocellular carcinoma, gastric cancer, acute myeloid leukemia, colorectal cancer, and papillary thyroid cancer (ELBassuoni et al., 2015; Hou and Yang, 2015; Lee et al., 2015; Ma et al., 2015; Omrane et al. (2015); Zhu et al., 2015). ELBassuoni et al. (2015) carried out a study on 35 hepatocellular carcinoma patients and 20 healthy subjects, which indicated that the GG genotype of IL17A was associated with an increased risk of hepatocellular carcinoma in an Egyptian population. Hou and Yang (2015) carried out a study on 326 gastric cancer patients and 326 controls, which revealed a significant association between the IL17A rs2275913G>A polymorphism and elevated gastric cancer risk. However, another study on 62 acute myeloid leukemia patients and 125 healthy controls indicated that IL17A genetic polymorphisms were not associated with the risk of this cancer (Zhu et al., 2015). Omrane et al. (2015) reported that IL17A and IL17F genes may be predictive factors for colorectal cancer therapy. Lee et al. (2015) reported that IL17A was not significantly associated with the risk of papillary thyroid cancer in a Korean population. Ma et al. (2015) indicated that IL17A-73G/A polymorphism contributes to the pathogenesis of non-small cell lung cancer.

The authors of five previous studies have reported an association between IL17A polymorphisms and cervical cancer (Quan et al., 2012; Cong et al., 2015; Li et al., 2015a; Lv et al., 2015; Sun et al., 2015). All the studies indicated that the IL17A rs2275913 polymorphism was associated with the risk of cervical cancer. Three studies revealed an association between the IL17A rs3748067 polymorphism and the risk of cervical cancer, but the correlation was not significant (Cong et al., 2015; Li et al., 2015a; Lv et al., 2015). However, they did not investigate the interaction between the IL17A polymorphism and environmental factors. We initially observed that the IL17A rs2275913 polymorphism was positively associated with HPV infection. Previous studies have shown that upregulation of IL17A expression is associated with HPV 16 infection with regard to the risk of cancers (Chang et al., 2010; Li et al., 2015b; Vidal et al., 2015). Further studies are needed to confirm our study.

One important limitation of our study should be considered. The cervical cancer patients and controls were recruited from only one hospital, which may have caused selection bias in our study. In conclusion, our study suggests that the IL17A rs3748067 polymorphism is independently associated with the risk of cervical cancer, and has a relationship with HPV infection with regard to the risk of cervical cancer.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

We thank for the great help from staffs in the First People’s Hospital of Shangqiu, and they help us to collect the blood sample for us.

About the Authors

Corresponding Author

A.Q. Niu

Department of Gynecology, The First People’s Hospital of Shangqiu, Shangqiu, China

Email:
[email protected]

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