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ISSN: 1948-593X
Journal of Bioanalysis & Biomedicine
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Current Evidence on the Association between Cytotoxic T-Lymphocyte Antigen 4 +49G > A Polymorphism and Digestive System Cancer Risks: a Meta-analysis Involving 11,923 Subjects

Biao Jiang, Meng Ji, Ailiang Wang, Wei Zhang, Zhixin Zhang and Qiang Li*

Tianjin Cancer Institute and Hospital, Tianjin, China

Corresponding Author:
Qiang Li
Tianjin Cancer Institute and Hospital
Tianjin, China
E-mail: [email protected]

Received date: March 22, 2013; Accepted date: April 27, 2013; Published date: April 30, 2013

Citation: Jiang B, Ji M, Wang A, Zhang W, Zhang Z, et al. (2013) Current Evidence on the Association between Cytotoxic T-Lymphocyte Antigen 4 +49G > A Polymorphism and Digestive System Cancer Risks: a Meta-analysis Involving 11,923 Subjects. J Bioanal Biomed S9: 002. doi: 10.4172/1948-593X.S9-002

Copyright: © 2013 Jiang B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) plays an important role in downregulating T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with many cancer types, but the association between CTLA-4 +49G > A polymorphism and digestive system cancer risks remain inconclusive. An updated meta-analysis based on 17 independent case-control studies consisting of 5,176 cancer patients and 6,747 controls was performed to address this association. Overall, there was no statistically increased risk of digestive system cancers in every genetic comparison.In subgroup analysis, this polymorphism was significantly linked to higherrisks for pancreatic cancer (GG vs. AA, OR=1.976, 95% CI = 1.496-2.611; GA vs. AA,
OR=1.433, 95% CI = 1.093-1.879; GG/GA vs. AA, OR=1.668, 95% CI = 1.286-2.164; GG vs. GA/AA, OR = 1.502, 95% CI = 1.098-2.054; G vs. A, OR=1.394, 95%CI = 1.098-1.770). We also observed increased susceptibility of hepatocellular cell carcinoma in homozygote comparison (OR=1.433, 95% CI = 1.100-1.866) and dominant model (OR=1.360, 95% CI = 1.059-1.746). According to the source of controls, significant effects were only observed in hospital-based studies (GA/AA vs. GG, OR=1.257, 95% CI = 1.129-1.399). In the stratified analysis by ethnicity, No significantly increased risks were
found in either Asian or Caucasian. Our findings suggest that the CTLA-4 +49G > A polymorphism may be not associated with an elevated digestive system cancer risks.

Keywords

CTLA-4; Polymorphisms; Cancer; Meta-analysis

Introduction

CTLA-4, a member of the immunoglobulin super-family, is a costimulatory molecule expressed by activated T cells and has the function of down-regulating T-cell activation [1]. CTLA-4 can also induce FAS-independent apoptosis of activated T cells, which may further inhibit immune function of T lymphocytes. A list of mechanisms of CTLA-4 function have been indicated, such as ligand competition with the positive T-cell co-stimulatory CD28 molecule, interference of TCR signaling, and inhibition of cyclin D3 and cyclin-dependent kinases production [2]. In tumor-transplanted mice, injection with antibodies that block CTLA-4 function enhanced T cell activation [3], rejected a variety of different tumors, and had long-lasting anti-tumor immunity [4], suggesting that the CTLA-4 may play an important role in carcinogenesis.

The CTLA-4 gene is located on chromosome 2q33, consisting 4 exons that encode separate functional domains: a leader sequence, an extracellular domain, a transmembrane domain, and a cytoplasmic domain [5-7]. This gene is polymorphic and more than 100 single nucleotide polymorphisms have been identified [8]. An common polymorphism at position 49 in CTLA-4 exon 1 (rs231775), which causes an amino acid change (threonine to alanine) in the peptide leader sequence of the CTLA-4 protein [9]. Recent studies indicated that this polymorphism may influence the ability of CTLA-4 to bind with B7.1 and affect T-cell activation subsequently [10,11].

Previous studies have identified that this polymorphism is associated with different cancers including lung cancer, breast cancer, and cervical cancer [10,12]. However, the results of studies on the association between the +49 A > G polymorphism and the risk of digestive system cancers remain inconsistent [10,13-26]. To improve the efficiency of meta-analysis on digestive cancers and reduce the potential between-study heterogeneity which might derive from various cancers in diverse systems, we focused on digestive system cancers only and added more recent studies in this meta-analysis.

Search Strategy

In this meta-analysis, a comprehensive literature research of the US National Library of Medicine’s Pub Med database, ISI Web of Knowledge, Medline, Embase and Google Scholar Search (update to November, 2012) were conducted using the search terms including ‘‘CTLA-4’’, ‘‘polymorphisms’’, ‘‘cancer’’, and the combined phrases in order to obtain all genetic studies on the relationship of CTLA-4 + 49G/A polymorphism and cancer. We also used a hand search of references of original studies or reviewed articles on this topic to identify additional studies. The following criteria was used to select the eligible studies: (1) a case–control study on the association between CTLA-4 + 49G/A polymorphism and cancer; (2) detailed number of different genotypes for estimating an odds ratio (OR) with 95% confidence interval; (3) when several publications reported on the same population data, the largest or most complete study was chosen.

Data Extraction

Data extraction was carried out independently by two investigators after the concealment of authors, journals, supporting organizations and funds to avoid investigators’ bias. For each eligible study, the following information was recorded: the first author’s name, the year of publication, country of origin, cancer type, genotyping method, sources of controls, racial descent of the study population, number of cases and number of controls with different allele frequencies.

Statistical Analysis

The strength of relationship between CTLA-4 + 49G/A polymorphism and cancer was assessed by using Crude OR with 95% CI. We examined the association between the CTLA-4 + 49G/A polymorphism and digestive cancer risks using the following genetic contrasts: homozygote comparison (GG vs. AA), heterozygote comparison (GA vs. AA), dominant genetic model (GG + GA vs. AA), recessive genetic model (GG vs. GA + AA) and allelic comparison (G vs. A). Between-study heterogeneity was evaluated by Q-test. Fixed effects model was used to pool the data when the P-value of Q-test ≥ 0.05, otherwise, random-effects model was selected. Both funnel plot and Egger’s test were used to assess the publication bias. (P<0.05 was considered representative of statistical significance). All statistical analyses were performed using STATA11.0 software and Review Manage (v.5; Oxford, England).

Results

Eligible studies

By the inclusion and exclusion criteria, 17 relevant studies involving 5,176 cases and 6,747 controls were selected in this metaanalysis. The main characteristics of these studies are shown in table 1. Genotype distribution of the CTLA-4 + 49G/A polymorphism among cancer cases and controls of the 17 studies are shown in table 2. All studies were case–control studies, including five colorectal cancer studies, four gastric cancer studies, two esophageal cancer studies, two hepatocellular cell carcinoma studies, two oral cancer studies and two pancreatic cancer studies. There were 12 studies of Asian descent and five studies of Caucasian descent. Hospital based controls were carried out in 12 studies, while population based controls were carried out in 5 studies. The genotyping method contains the classic polymerase chain reaction–restriction fragment length polymorphism assay(PCR-RFLP), RFLP and Taqman. The distribution of genotypes in the controls was all in agreement with HWE.

Author Year Type Ethnicity Country Genotye Assay Source of
Control
Cases Controls
Yang 2012 Pancreatic Asian China PCR-RFLP Population 926 368
Lang 2012 Pancreatic Asian China PCR-RFLP Population 651 602
Cheng 2011 Esophagus Asian China PCR-RFLP Population 205 205
Cozar 2007 Colon, European Spain TaqMan Hospital 176 221
Dilmec 2008 Colorectal European Turkey RFLP Hospital 162 56
Gu 2010 Hepatocellular Asian China PCR-LDR Hospital 367 407
Hadinia 2007 Colorectal Asian Iran RFLP, PCR-ARMS Hospital 190 105
Hadinia 2007 Gastric Asian Iran RFLP, PCR-ARMS Hospital 190 43
Hu 2010 Hepatocellular Asian China TaqMan Population 854 853
Hou 2010 Gastric Asian China PCR-ARMS NA 205 262
Kammerer 2010 Oral European German RT-PCR Hospital 40 83
Mahajan 2008 Gastric European Poland TaqMan Population 411 301
Qi 2010 Colorectal Asian China PCR-LDR NA 124 407
Solerio 2005 Colorectal European Italy RFLP Hospital 238 132
Sun 2008 Esophagus Asian China RFLP Hospital 1008 1010
Sun 2008 Gastric Asian China RFLP Hospital 530 530
Wong 2006 Oral Asian China RFLP Hospital 147 118

Table 1: Main characteristics of included studies in the meta-analysis.

Author Year Type AA (control) AG (control) GG (control AA (case) AG (case) GG (case) G (control) A (control G (case) A (case) HWE
Gu 2010 Hepatocellular 51 166 150 45 179 183 268 466 269 545 YES
Hu 2010 Hepatocellular 106 380 367 79 376 399 592 1114 534 1174 YES
Hadinia 2007 Gastric 24 13 6 117 59 14 25 61 87 293 YES
Mahajan 2008 Gastric 89 153 59 152 189 70 331 271 493 329 YES
Hou 2010 Gastric 100 55 107 41 70 94 269 255 258 152 YES
Sun 2008 Gastric 60 235 235 39 209 282 355 705 287 773 YES
Qi 2010 Colorectal 4 60 60 45 179 183 68 180 269 545 YES
Solerio 2005 Colorectal 76 43 13 128 91 19 195 69 347 129 YES
Hadinia 2007 Colonrectal 52 47 6 117 59 14 59 151 87 293 YES
Cozar 2007 Colorectal 119 87 15 78 77 21 325 117 233 119 YES
Dilmec 2008 Colorectal 36 19 1 108 43 11 21 91 65 259 YES
Cheng 2011 Esphogaous 36 79 90 46 105 54 259 151 213 197 YES
Sun 2008 Esphogaous 128 434 448 73 406 529 690 1330 552 1464 YES
Kammerer 2010 Oral 35 32 16 11 23 6 102 64 45 35 YES
Wong 2006 Oral 12 58 48 25 64 58 82 154 114 180 YES
Yang 2012 Pancreatric 50 178 140 70 374 482 458 278 1338 514 YES
Lang 2012 Pancreatric 82 312 208 62 326 263 728 476 852 450 YES

Table 2: Distribution of CTLA-4 + 49G/A polymorphism among cancer cases and controls in this meta-analysis.

Meta-analysis

The association strength between CTLA-4 + 49G/A polymorphism and the susceptibility for digestive system cancers are shown in table 3. Overall, there was no statistically increased risk of digestive system cancers in every genetic comparison (GG vs. AA, OR=1.217, 95% CI = 0.923–1.605; GA vs. AA, OR=1.161, 95% CI = 0.991–1.360; GG/GA vs. AA, OR=1.165, 95% CI = 0.932–1.456; GG vs. GA/AA, OR=1.114, 95% CI = 0.948–1.312; G vs. A, OR= 0.966, 95% CI = 0.829–1.126).

Study groups N * GG vs. AA GA vs. AA GG/GA vs. AA GG vs. GA/AA G vs. A
OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P
Total 17 1.217 (0.923-1.605) ‡ <0.001 1.161 (0.991-1.360)‡ <0.001 1.165 (0.932-1.456)‡ <0.001 1.114 (0.948-1.312)‡ <0.001 0.966 (0.829-1.126)‡ <0.001
Cancer type                      
Hepatocellular 2 1.433 (1.100-1.866) 0.851 1.291 (0.992-1.681) 0.771 1.360 (1.059-1.746) 0.796 1.168 (0.996-1.367) 0.920 0.857 (0.761-0.964) 0.983
Gastric 4 1.160 (0.601-2.237)‡ <0.001 1.300 (0.670-2.521)‡ <0.001 1.235 (0.662-2.302)‡ <0.001 1.077 (0.814 -1.508) ‡ 0.042 1.033 (0.696-1.532)‡ <0.001
Colorectal 5 1.028 (0.479-2.207)‡ 0.020 0.805 (0.498- 1.301)‡ 0.006 0.858 (0.543-1.354)‡ 0.006 1.079 (0.804-1.447) 0.215 0.929 (0.727-1.188)‡ 0.060
Esophagus 2 1.004 (0.235-4.295)‡ <0.001 1.454 (1.110-1.906) 0.146 1.194 (0.482-2.957)‡ 0.002 0.809 (0.273-2.398)‡ <0.001 0.708 (0.627-0.799) 0.368
Oral 2 0.725 (0.379-1.385) 0.312 1.086 (0.259-4.554)‡ 0.013 1.017 (0.300-3.449)‡ 0.026 0.876 (0.563-1.364) 0.478 1.058 (0.786-1.424) 0.240
Pancreatic 2 1.976 (1.496-2.611) 0.173 1.433 (1.093-1.879) 0.766 1.668 (1.286-2.164) 0.347 1.502 (1.098-2.054)‡ 0.033 1.394 (1.098-1.770)‡ 0.049
Ethnicity                      
Asian 12 1.240 (0.908-1.695)‡ <0.001 1.164 (0.895- 1.514)‡ <0.001 1.179(0.896-1.551)‡ <0.001 1.139 (0.956 -1.356)‡ <0.001 0.974 (0.807-1.175)‡ <0.001
European 5 1.143 (0.660-1.977)‡ 0.043 0.988 (0.699-1.397)‡ 0.021 1.101(0.776-1.562)‡ 0.029 1.015 (0.763 -1.351) 0.154 0.951 (0.745-1.213) 0.053
Source of Control                      
Population-based 5 1.169 (0.694-1.970)‡ <0.001 1.156 (0.873-1.530)‡ 0.029 1.170(0.800-1.712)‡ <0.001 0.965 (0.678-1.373)‡ <0.001 1.063 (0.802-1.408)‡ <0.001
Hospital-based 12 1.255 (0.901-1.749)‡ 0.001 1.125 (0.828-1.530)‡ <0.001 1.154(0.864-1.541)‡ <0.001 1.257 (1.129-1.399) 0.150 0.919 (0.778-1.086)‡ <0.001

Table 3: Results of meta-analysis for CTLA-4 + 49G/A polymorphism and digestive cancer risks.

We then evaluated the effects of CTLA-4 + 49G/A polymorphism according to specific cancer types, different ethnicities and different sources of control. As shown in table 3, we demonstrated that this locus polymorphism was significantly linked to higherrisks for pancreatic cancer (GG vs. AA, OR=1.976, 95% CI = 1.496-2.611; GA vs. AA, OR=1.433, 95% CI = 1.093-1.879; GG/GA vs. AA, OR=1.668, 95% CI =1.286-2.164; GG vs. GA/AA, OR=1.502, 95% CI = 1.098- 2.054; G vs. A, OR=1.394, 95%CI = 1.098-1.770). We alsoobserved increased susceptibility of hepatocellular cell carcinoma in homozygote comparison (OR=1.433, 95% CI = 1.100-1.866) and dominant model (OR = 1.360, 95% CI = 1.059-1.746). Furthermore, we observed increased susceptibility of esophageal cancer only in heterozygote comparison (OR=1.454, 95% CI = 1.110-1.906). No significant associations were found in colorectal cancer, gastric cancer and oral cancer.

According to the source of controls, significanteffects were observed in hospital-based studies (GA/AA vs. GG, OR=1.257, 95% CI = 1.129- 1.399), but in population-based studies, no significant association was observed in all models. In the stratified analysis by ethnicity, no significantly increased risks were found in either Asian or Caucasian.

Publication bias

Both Begg’s funnel plot and Egger’s test were performed to assess the publication bias of the literature. The shape of the funnel plots did not reveal any evidence of obvious asymmetry in the overall metaanalysis (Figure 1 shows the funnel plot of overall GG vs. AA). Then, Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results still did not present any obvious evidence of publication bias in the subgroup analyses.

bioanalysis-biomedicine-funnelplot

Figure 1: The funnel plot of overall GG vs. AA.

Discussion

The result of this meta-analysis suggested that CTLA-4 + 49G/A polymorphism was not overall significantly associated with digestive system cancer risk. In stratified analysis by ethnicity, we also failed to detect any significant association in either Asian or Caucasian. However, in subgroup analysis, this polymorphism was significantly linked to higher risks for pancreatic cancer. Besides, when stratified according to study design, positive associations were observed in hospital-based studies.

The CTLA-4 49G>A SNP has been linked to elevated risk of breast cancer in an Iranian population [6], and non–Hodgkin’s lymphoma in an European Caucasian population [26]. In addition, two more studies suggested that this polymorphism is associated with different cancers including lung cancer and cervical cancer [10,21]. A metaanalysis conducted by Zheng et al. suggested that the CTLA-4 + 49G/A polymorphism was associated with an increased risk of developing solid tumors (including lung cancer, breast cancer, colorectal cancer, gastric cancer, skin cancer, thymoma, nasopharyngeal carcinoma, cervical squamous cell carcinoma, esophageal cancer, oral squamous cell carcinoma, HBV-related hepatocellular carcinoma, and renal cell cancer [27]. Interestingly, Zhang et al. conducted a meta-analysis and the results indicated that the polymorphism is associated with a decreased risk of lung cancer and breast cancer but not of cervical cancer, colorectal cancer, or gastric cancer [28].

In our analysis, we first reported that there was no statistically increased risk between the CTLA-4 + 49G/A polymorphism and digestive system cancers. In subgroup analysis, we observed this polymorphism was significantly linked to higher risks for pancreatic cancer. We also observed the CTLA-4 + 49G/A polymorphism was associated with an increased risk of developing hepatocellular cell carcinoma but not gastric cancer, colorectal cancer and oral cancer. However, all of these results should be interpreted with caution. On condition that, for some cancer types, only two case-control studies were included, which may have limited power to reveal a reliable association. Furthermore, we observed inconsistent results between hospital-based studies and population-based studies, which may be explained by the biases brought by hospital-based studies, controls in hospital-based studies may be less representative of general population than controls from population-based studies.

There were some limitations in our meta-analysis. Firstly, sample size in any given cancer was not sufficiently large. It might be difficult to get a concrete conclusion if the number of included studies in subgroup was few. Secondly, due to the original data of the eligible studies were unavailable, it is difficult for us to evaluate the roles of some special environmental factors and lifestyles such as diet, alcohol consumption, and smoking status in developing cancer. And thirdly, language bias might derive from the screened references of English documents only.

In conclusion, our meta-analysis suggested that the CTLA-4 + 49G/A polymorphism may be not associated with an elevated digestive system cancer risks. Large well-designed epidemiological studies are needed to validate our findings.

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