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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 526-532

Association of cytotoxic T-lymphocyte antigen 4 rs231775 gene polymorphism with colorectal cancer risk


1 Department of Interventional Oncology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
2 Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian 351100, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Zhiyong Dong
Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian 351100
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191065

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 > Abstract 

Aim of the Study: Results on the relationship between cytotoxic T-lymphocyte antigen 4 (CTLA4) +49A/G (rs231775) gene polymorphism and colorectal cancer risk are still debated. This meta-analysis was performed to assess the association between CTLA4 +49A/G and colorectal cancer risk.
Materials and Methods: The relevant studies were searched from PubMed, Cochrane Library, and China Biological Medicine Database-disc, and eligible investigations were included and synthesized using meta-analysis method.
Results: Eleven studies were recruited into this meta-analysis for the association of CTLA4 A/G gene polymorphism and colorectal cancer risk, consisting of 1802 colorectal cancer patients and 2939 controls. G allele was a risk factor for the colorectal cancer risk, and AA genotype might be a protective factor against colorectal cancer risk in overall populations (G allele: Odds ratio [OR] = 1.19, 95% confidence interval [CI]: 1.03–1.38, P = 0.02; AA genotype: OR = 0.63, 95% CI: 0.47–0.84, P = 0.002). However, the GG genotype was not associated with colorectal cancer risk in overall populations.
Conclusion: The association between CTLA4 G allele/AA genotype and colorectal cancer risk was found in this meta-analysis.

Keywords: A/G gene polymorphism, colorectal cancer, cytotoxic T-lymphocyte antigen 4, meta-analysis, rs231775


How to cite this article:
Zhang Y, Zhang S, Xia W, Dong Z. Association of cytotoxic T-lymphocyte antigen 4 rs231775 gene polymorphism with colorectal cancer risk. J Can Res Ther 2018;14, Suppl S2:526-32

How to cite this URL:
Zhang Y, Zhang S, Xia W, Dong Z. Association of cytotoxic T-lymphocyte antigen 4 rs231775 gene polymorphism with colorectal cancer risk. J Can Res Ther [serial online] 2018 [cited 2019 Jul 20];14:526-32. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/526/191065


 > Introduction Top


Colorectal cancer, one of the most common malignancies worldwide, is a leading cause of cancer death. Despite decades of intensive investigations, effective interventional options are still limited and colorectal cancer patient prognosis remains poor.[1] A wide spectrum of biomarkers is used for molecular subtype determination, prognosis, and estimation of sensitivity to different drugs in practice.[2]

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a regulatory molecule, suppresses T-cell effector function, following initial activation by costimulatory signals.[3] The present evidence indicates that CTLA4 can take part in the pathogenesis of colorectal cancer. The CTLA4 +49A/G gene polymorphism is polymorphic with an A to G transition, and the present evidence shows that CTLA4 +49A/G (rs231775) gene polymorphism is associated with the risk of colorectal cancer.

In previous, some meta-analysis assessed the relationship between CTLA4 +49A/G gene polymorphism and the risk of colorectal cancer. However, the sample size of those meta-analyses was small. This meta-analysis was performed to investigate whether the CTLA4 +49A/G gene polymorphism was associated with the risk of colorectal cancer.


 > Materials and Methods Top


Search strategy

The relevant studies were searched from the electronic databases of PubMed, Cochrane Library, and China Biological Medicine Database-disc on May 1, 2016. The retrieval strategy of “cytotoxic T-lymphocyte antigen 4 OR CTLA4 AND polymorphism OR polymorphisms OR genotype OR genotypes OR allele OR alleles AND colorectal adenoma OR colorectal cancer” was entered into these databases. The additional reports were identified through references cited in recruited articles.

Inclusion and exclusion criteria

Inclusion criteria

  • The outcome had to be colorectal cancer; (2) there had to be at least two comparison groups (colorectal cancer group vs. control group); (3) investigation should provide the data of CTLA4 +49A/G genotype distribution.


Exclusion criteria

  • Review articles and editorials; (2) case reports; (3) preliminary result not on CTLA4 +49A/G gene polymorphism or outcome; (4) investigating the role CTLA4 gene expression to disease.


Data extraction

The following information from each eligible study was extracted independently by two investigators: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 (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 (ORs) 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. Sensitivity analysis was also performed according to source of the controls (population-based [PB] vs. hospital-based [HB]). Stata 11.0 (Stata Corporation, College Station, TX) was used to test the publication bias. The Begg adjusted rank correlation test [4] and the Egger regression asymmetry test [5] were used to evaluate the publication bias (P < 0.1 was considered statistically significant).


 > Results Top


Study characteristics

Eleven studies [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] reporting the relationship between CTLA4 +49A/G gene polymorphism and colorectal cancer 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 and control groups were calculated. The study characteristics of the included studies were presented in

[Table 1]. Those 11 investigations contained 1802 colorectal cancer patients and 2939 controls.
Table 1: Characteristics of the studies evaluating the effects of cytotoxic T-lymphocyte antigen 4+49A/G gene polymorphism on colorectal cancer risk

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Association of cytotoxic T-lymphocyte antigen-4 +49A/G gene polymorphism with colorectal cancer

In this meta-analysis, we found that CTLA4 +49A/G G allele was associated with colorectal cancer risk in overall populations (OR = 1.19, 95% CI: 1.03–1.38, P = 0.02) [Figure 1] and [Table 2]. Furthermore, AA seemed to play a protective role against colorectal cancer (OR = 0.63, 95% CI: 0.47–0.84, P = 0.002) [Figure 1] and [Table 2]. However, the GG genotype was no a risk factor for colorectal cancer (OR = 0.95, 95% CI: 0.73–1.24, P = 0.71) [Figure 1] and [Table 2].
Figure 1: Association between cytotoxic T-lymphocyte antigen 4 +49A/G gene polymorphism and colorectal cancer risk (overall populations)

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

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In the subgroup analysis, according to the ethnicity, this meta-analysis indicated that CTLA4 +49A/GG allele/AA genotype was associated with colorectal cancer risk in the Asian population and this association for GG genotype was not found [Figure 2] and [Table 2].
Figure 2: Association between cytotoxic T-lymphocyte antigen 4 +49A/G gene polymorphism and colorectal cancer risk (Asian population)

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However, this meta-analysis indicated that CTLA4 +49A/G gene polymorphism was not associated with colorectal cancer in Caucasians [Figure 3] and [Table 2].
Figure 3: Association between cytotoxic T-lymphocyte antigen 4 +49A/G gene polymorphism and colorectal cancer risk (Caucasian population)

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Sensitivity analysis

Sensitivity analysis for the relationship between CTLA4 +49A/G gene polymorphism and colorectal cancer risk was also performed according to the source of the controls (PB vs. HB), and sensitivity analysis for the relationship between CTLA4 +49A/G gene polymorphism and colorectal cancer risk according to HB was not found [Table 2]. However, in the sensitivity analysis, according to PB, AA genotype seemed to play a protective role against colorectal cancer risk, but this association for G allele and GG genotype was not found [Table 2].

Evaluation of publication bias

Publication bias was not showed for the overall populations [Begg P = 0.436, funnel plot was presented in [Figure 4]; Egger P = 0.232].
Figure 4: Funnel plot to assess publication bias for the association of cytotoxic T-lymphocyte antigen 4 +49A/G gene polymorphism with colorectal cancer risk in overall populations

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 > Discussion Top


Association of CTLA4 +49A/GG allele/AA genotype with the risk of colorectal cancer was observed in overall populations from this meta-analysis. We also test the publication bias and found that there was no publication bias for the analysis of the association of CTLA4 +49A/G gene polymorphism with the risk of colorectal cancer in overall populations. The conclusion for the association of CTLA4 +49A/G gene polymorphism with the risk of colorectal cancer in overall populations was robust to some extent.

Interestingly, we found that G allele and AA genotype were associated with the risk of colorectal cancer in Asian population, and there were seven included studies for Asians. It seemed that the conclusion for Asian population was robust to some extent. However, more studies should be conducted to explore this association in Asians.

However, in the subgroup analysis, we found that there was no an association between CTLA4 +49A/G gene polymorphism and the risk of colorectal cancer in Caucasians. The number of included studies for Caucasians was small. More studies should be performed in the future.

Sensitivity analysis for the relationship between CTLA4 +49A/G gene polymorphism and colorectal cancer risk was also performed according to the source of the controls (PB vs. HB), and sensitivity analysis for the relationship between CTLA4 +49A/G gene polymorphism and colorectal cancer risk according to HB was not found. However, in the sensitivity analysis, according to PB, AA genotype seemed to play a protective role against colorectal cancer risk. More studies should be conducted in the future.

He et al.[17] performed a meta-analysis including eight studies and reported that CTLA-4 +49A/G polymorphism significantly increases the risk of colorectal cancer, especially for Asians. Xiaolei et al.[18] conducted a meta-analysis recruited five studies and the results indicated that GG genotype and AA genotype were associated with colorectal cancer in overall populations. The number of included studies in our meta-analysis was much larger (11 included studies) than the previous meta-analyses, and our results might be more robust than those from the above-mentioned meta-analyses.


 > Conclusion Top


The results in our meta-analysis indicated that CTLA4 +49A/GG allele/AA genotype was associated with the risk of colorectal cancer in the Asian population and overall populations. However, more association studies are required to further clarify this association.

Financial support and sponsorship

The study was supported by grants from Natural Science Foundation of China (No. 81371597) and Shanghai Natural Science Foundation (13ZR1431900).

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101.  Back to cited text no. 4
    
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Dilmec F, Ozgonul A, Uzunkoy A, Akkafa F. Investigation of CTLA-4 and CD28 gene polymorphisms in a group of Turkish patients with colorectal cancer. Int J Immunogenet 2008;35:317-21.  Back to cited text no. 9
    
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Li X, Zhao J, Sun Y. Relationship between cytotoxic T-lymphocyte associated antigen-4+49A>G gene polymorphism and colorectal cancer in Chinese. Chin J Biol 2011;24:1038-41.  Back to cited text no. 11
    
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Cui J, Ma H, Cui W, Ma W, Qi Y. Association of cytotoxic T-lymphocyte antigen-4 gene polymorphism with susceptibility on colorectal cancer. Chin J Curr Adv Gen Surg 2013;16:127-30.  Back to cited text no. 13
    
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Wang Y, Wang X, Zhao R. The association of CTLA-4 A49G polymorphism with colorectal cancer risk in a Chinese Han population. Int J Immunogenet 2015;42:93-9.  Back to cited text no. 14
    
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Li X, Zhao L, Zhong H, Fang T, Liu W. Correlative study on CTLA-4+49A>G polymorphism Gene polymorphism and colorectal cancer. Prog Mod Biomed 2015;15:822-4.  Back to cited text no. 15
    
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Kucukhuseyin O, Turan S, Yanar K, Arikan S, Duzkoylu Y, Aydin S, et al. Individual and combined effects of CTLA4-CD28 variants and oxidant-antioxidant status on the development of colorectal cancer. Anticancer Res 2015;35:5391-400.  Back to cited text no. 16
    
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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. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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