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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1117-1120

Association of cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism with hepatocellular carcinoma risk in Chinese


Department of Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China

Date of Web Publication11-Dec-2018

Correspondence Address:
Zhiyong Dong
Department of Surgery, The First Affiliated Hospital of Jinan University, No.613, Huangpu Avenue West, Guangzhou 510630
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.203604

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 > Abstract 


Aim of Study: Hepatocellular carcinoma (HCC), a common cause of cancer-associated mortalities worldwide, is a complex polygenic disease, and its development is dependent on many genetic factors. Hepatitis B virus infection, also called chronic hepatitis B (CHB), is the leading cause of HCC. This meta-analysis was performed to assess the association between cytotoxic T-lymphocyte antigen-4 (CTLA4) +49A/G and HCC risk.
Materials and Methods: The association studies were recruited from PubMed and China Biological Medicine Database, and eligible studies were included and synthesized using meta-analysis method.
Results: Four reports were included into this meta-analysis for the association of CTLA4 A/G gene polymorphism and HCC risk, and all the included studies were from Chinese. The association between CTLA4 A/G gene polymorphism and HCC risk was found in this meta-analysis (G allele: odds ratio [OR] =1.21, 95% confidence interval [CI]: 1.03–1.44, P = 0.02; GG genotype: OR = 1.21, 95% CI: 1.03–1.44, P = 0.02; AA genotype: OR = 1.37, 95% CI: 1.10–1.69, P = 0.004). Furthermore, G allele and GG genotype were associated with the CHB patients developing into HCC (G allele: OR = 0.81, 95% CI: 0.66–0.98, P = 0.03; GG genotype: OR = 0.75, 95% CI: 0.57–0.99, P = 0.04).
Conclusion: CTLA4 A/G gene polymorphism was associated with HCC risk and CTLA4 G allele/GG genotype is associated with CHB patients developing into HCC in Chinese.

Keywords: A/G gene polymorphism, chronic hepatitis B, cytotoxic T-lymphocyte antigen-4, hepatocellular carcinoma, meta-analysis


How to cite this article:
Wang C, Liu W, Zhao L, Dong Z. Association of cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism with hepatocellular carcinoma risk in Chinese. J Can Res Ther 2018;14, Suppl S5:1117-20

How to cite this URL:
Wang C, Liu W, Zhao L, Dong Z. Association of cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism with hepatocellular carcinoma risk in Chinese. J Can Res Ther [serial online] 2018 [cited 2019 Sep 15];14:1117-20. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1117/203604




 > Introduction Top


Hepatocellular carcinoma (HCC) is a common cause of cancer-associated mortalities worldwide, and its prevalence is expected to increase in future decades.[1],[2] Hepatitis B virus infection, also called chronic hepatitis B (CHB), is the leading cause of HCC. The pathogenesis of HCC is mainly characterized by persistent cycles of liver injury, inflammation, and compensatory hepatocyte proliferation.[3] HCC is a complex polygenic disease, and its development is dependent on many genetic factors.[4]

Cytotoxic T-lymphocyte antigen-4 (CTLA4, CD152), an immune checkpoint molecule, is a CD28 homolog that binds the ligands B7-1 (CD80) and B7-2 (CD86). Protein expression of CTLA4 in cancer appears to be important for tumors to evade host immune surveillance.[5] The clinical implications of CTLA4 expression in tumors or immune cells in the tumor microenvironment are still controversial. The CTLA4 + 49A/G gene polymorphism is polymorphic with an A to G transition. Present evidence indicates that CTLA4 + 49A/G gene polymorphism might be associated with the HCC risk.

This meta-analysis was performed to assess whether the CTLA4 + 49A/G gene polymorphism was associated with the HCC risk.


 > Materials and Methods Top


Search strategy

The included studies were searched from the electronic databases of PubMed and China Biological Medicine Database on June 1, 2016. The retrieval strategy of “(cytotoxic T-lymphocyte antigen-4 OR CTLA4) AND polymorphism AND (hepatocellular carcinoma OR hepatocarcinoma)” was entered into the above database.

Inclusion criteria

  • The outcome had to be HCC risk
  • There had to be at least two comparison groups (HCC group vs. control group)
  • Investigation should provide the data of CTLA4 + 49A/G genotype distribution.


Exclusion criteria

  • Review articles, editorials, case reports
  • Preliminary result not on CTLA4 + 49A/G gene polymorphism or its outcome
  • Investigating the role CTLA4 gene expression to the disease.


Data extraction

The following information from each eligible study was extracted independently: first author's surname, year of publication, ethnicity, control source of the control group, and the number of cases and controls for CTLA4 + 49A/G genotypes. Frequencies of G allele of CTLA4 + 49A/G were calculated for case group and control group, from the corresponding genotype distribution. The results were compared and disagreement was resolved by discussion.

Statistical analysis

Cochrane Review Manager Version 5.1 (Cochrane Library, UK) was used to calculate the available data from each investigation. The pooled statistic was counted using the fixed effects model, but a random effects model was conducted when the P value of heterogeneity test was <0.1. Results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CIs) were also calculated. P < 0.05 was required for the pooled OR to be statistically significant. I2 was used to test the heterogeneity among the included studies.


 > Results Top


Study characteristics

Four studies[6],[7],[8],[9] reporting the relationship between CTLA4 + 49A/G gene polymorphism and HCC risk were recruited into this meta-analysis. The data of our interest were extracted, and the frequencies of G allele of CTLA4 + 49A/G for case group and control group were calculated. The study characteristics of the included studies were presented in [Table 1].
Table 1: Characteristics of the studies evaluating the effects of cytotoxic T-lymphocyte antigen-4 +49A/G gene polymorphism on hepatocellular carcinoma risk

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Association of cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism with hepatocellular carcinoma risk (healthy control)

In this meta-analysis, we found that CTLA4 + 49A/G G allele/GG genotype was associated with HCC risk (G allele: OR = 1.21, 95% CI: 1.03–1.44, P = 0.02; GG genotype: OR = 1.21, 95% CI: 1.03–1.44, P = 0.02) [Figure 1] and [Table 2]. However, the AA genotype seemed to be a risk factor for HCC risk (OR = 1.37, 95% CI: 1.10–1.69, P = 0.004) [Figure 1] and [Table 2].
Figure 1: Association between cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism and hepatocellular carcinoma risk (healthy)

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Table 2: Meta-analysis of the association of cytotoxic T-lymphocyte antigen-4 +49A/G gene polymorphism with hepatocellular carcinoma risk

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Association of cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism with hepatocellular carcinoma risk (chronic hepatitis B control)

CTLA4 + 49A/G G allele/GG genotype might be a protective factor against HCC risk (G allele: OR = 0.81, 95% CI: 0.66–0.98, P = 0.03; GG genotype: OR = 0.75, 95% CI: 0.57–0.99, P = 0.04) [Figure 2] and [Table 2]. However, AA genotype was not associated with HCC risk (OR = 1.23, 95% CI: 0.85–1.76, P = 0.27) [Figure 2] and [Table 2]. It indicated that G allele and GG genotype were associated with the CHB patients developing into HCC.
Figure 2: Association between cytotoxic T-lymphocyte antigen-4 + 49A/G gene polymorphism and hepatocellular carcinoma risk

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 > Discussion Top


In this meta-analysis, all the included studies were from the Chinese population. The results indicated that CTLA4 + 49A/G G allele/GG genotype was a protective factor against HCC risk. However, the GG genotype seemed to be a risk factor for HCC risk when we calculate the results using the healthy controls. There was heterogeneity for the analysis of G allele/GG genotype. When we used the fixed model to test them, the results were similar to those form random model (data not shown). The conclusion for the association of CTLA4 + 49A/G G allele/GG genotype with the HCC risk was robust to some extent.

Interestingly, we found that CTLA4 + 49A/G G allele/GG genotype might be a protective factor against HCC risk when the controls from CHB in Chinese. It indicated that G allele/GG genotype was associated with the CHB patients developing into HCC in Chinese. However, there were only two included studies for this association analysis. More studies should be performed in the future.

In previous, Xiaolei et al.[10] conducted a meta-analysis and included two eligible studies to study the association between CTLA4 + 49A/G gene polymorphism and the risk of HCC and reported that G allele, GG genotype, and AA genotype were not associated with the risk of HCC. The sample size in our meta-analysis was larger than the previous meta-analysis, and the results in this meta-analysis were more robust than those form the above-mentioned meta-analysis.


 > Conclusion Top


The results in our meta-analysis support that CTLA4 A/G gene polymorphism was associated with HCC risk and CTLA4 G allele/GG genotype is associated with CHB patients developing into HCC in Chinese. However, more association investigations are required to further clarify this association.

Financial support and sponsorship

This study was supported by the Science and Technology Project of Putian University. No. 2013035.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Gong WF, Zhong JH, Xiang BD, Li LQ. Feasibility of combining adjuvant transarterial chemoembolization with nucleos (t) ide analog therapy for patients with HBV-associated hepatocellular carcinoma after hepatectomy. Mol Clin Oncol 2016;5:3-6.  Back to cited text no. 1
    
2.
Tian XC, Liu XL, Zeng FR, Chen Z, Wu DH. Platelet-to-lymphocyte ratio acts as an independent risk factor for patients with hepatitis B virus-related hepatocellular carcinoma who received transarterial chemoembolization. Eur Rev Med Pharmacol Sci 2016;20:2302-9.  Back to cited text no. 2
    
3.
Ji Y, Wang Z, Li Z, Zhang A, Jin Y, Chen H, et al. Angiotensin II enhances proliferation and inflammation through AT1/PKC/NF-x03BA; B signaling pathway in hepatocellular carcinoma cells. Cell Physiol Biochem 2016;39:13-32.  Back to cited text no. 3
    
4.
Sui ZY, Li J, Cheng GL, Wang SF. A single nucleotide polymorphism in the promoter region (rs10877887) of let-7 is associated with hepatocellular carcinoma in a Chinese population. Genet Mol Res 2016;15:1-6.  Back to cited text no. 4
    
5.
Zhang XF, Pan K, Weng DS, Chen CL, Wang QJ, Zhao JJ, et al. Cytotoxic T lymphocyte antigen-4 expression in esophageal carcinoma: Implications for prognosis. Oncotarget 2016;7:26670-9.  Back to cited text no. 5
    
6.
Liu Z, Song Z, Sun J, Sun F, Li C, Sun J, et al. Association between CTLA-4 rs231775 polymorphism and hepatocellular carcinoma susceptibility. Int J Clin Exp Pathol 2015;8:15118-22.  Back to cited text no. 6
    
7.
Liu G, Lu GX. Association of CTLA4 gene+49G/A polymorphism with HBV infection and HBV-related hepatocellular carcinoma in Hunan Han population. Nan Fang Yi Ke Da Xue Xue Bao 2010;30:1838-40.  Back to cited text no. 7
    
8.
Hu L, Liu J, Chen X, Zhang Y, Liu L, Zhu J, et al. CTLA-4 gene polymorphism+49 A/G contributes to genetic susceptibility to two infection-related cancers-hepatocellular carcinoma and cervical cancer. Hum Immunol 2010;71:888-91.  Back to cited text no. 8
    
9.
Gu X, Qi P, Zhou F, Ji Q, Wang H, Dou T, et al. +49G>A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population. Hum Immunol 2010;71:83-7.  Back to cited text no. 9
    
10.
Xiaolei L, Baohong Y, Haipeng R, Shuzhen L, Jianfeng G, Xiangpo P, et al. Current evidence on the cytotoxic T-lymphocyte antigen 4+49G>A polymorphism and digestive system cancer risks: A meta-analysis involving 11,923 subjects. Meta Gene 2015;6:105-8.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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