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International Journal of Clinical and Experimental Medicine logoLink to International Journal of Clinical and Experimental Medicine
. 2015 Aug 15;8(8):13282–13288.

Association of programmed death-1 gene polymorphism rs2227981 with tumor: evidence from a meta analysis

Umarjan Mamat 1, Muyassar Arkinjan 2
PMCID: PMC4612939  PMID: 26550254

Abstract

To investigate the association of programmed death-1 gene polymorphism rs2227981 with tumor risk. The PubMed, Medline, Ovid Medline, EMBASE, Web of Knowledge were searched. Meta-analyses were conducted using RevMan 5.2.2 software. Total six researches involving in a total of 1427 tumor patients and 1811 healthy control people were included into this meta analysis. There was no association of PD-1 gene polymorphism with total tumor risk under four genetic models. (CT+TT vs CC, OR=1.09, 95% CI=0.80-1.49, P=0.59; CT+CC vs TT, OR=0.93, 95% CI=0.52-1.66, P=0.61; TT vs CC, OR=0.99, 95% CI=0.57-1.72, P=0.97; CT vs CC, OR=1.16, 95% CI=0.80-1.70, P=0.43). The sub-group analysis shown there were a significantly difference on association of PD-1 gene polymorphism with digestive system tumor risk between tumor patients and healthy control people, except recessive model. (CT+TT vs CC, OR=1.57, 95% CI=1.20-2.07, P=0.001; TT vs CC, OR=1.67, 95% CI=1.12-2.49, P=0.01; CT vs CC, OR=1.51, 95% CI=1.13-2.01, P=0.005). Moreover, the meta analysis results shown that there were association of PD-1 gene polymorphism with tumor risk under two models for the tumor specific occurring only in women. (CT+TT vs CC, OR=0.80, 95% CI=0.67-0.95, P=0.01; TT vs CC, OR=0.61, 95% CI=0.44-0.83, P=0.002). This study suggests that PD-1 gene polymorphism rs2227981 is associated with specific tumor types, including digestive system tumor and tumor specific occurring in woman.

Keywords: Programmed death-1, polymorphism, tumor, genetic models, RevMan, meta analysis

Introduction

Lots of factors involves in cause of tumor, including infectious aspects, environment factors, and genetic factors [1-3]. Human immune system plays an important role in resisting tumors, of which the T lymphocyte is the most important anti-tumor immune regulator. Therefore, it is suggest that some immune response-related genes polymorphisms may contribute to tumor pathogenesis.

Programmed death-1 (PD-1), a 55 KDa type I transmembrane glycoprotein, is a potent immunoregulatory molecule expressed on lots of cells, including natural killer T cells (NKTs), monocytes, activated T and B lymphocytes [4]. As we know, PD-1 plays a crucial role in assisting cancer cell to escape the host immune system. Inhibition of PD-1 can improve the anti-tumor activity of immune system [5]. Other study reported that PD-1 is involved in the arthritis, which indicated that PD-1 may play a center role in development of autoimmune disease [6]. Moreover, there was a evidence that PD-1 gene polymorphism is associated with susceptibility of systemic lupus erythematosus [7]. Moreover, more and more studies have focus on the rheumatoid arthritis [8], type 1 diabetes [9] and ankylosing spondylitis [10], however, little is known the relationship between PD-1 gene polymorphism with tumor susceptibility, especially PD-1 rs2227981 (+7785).

The aim of this meta analysis was to comprehensively and quantitatively summarize the all world results to evaluated PD-1 gene polymorphism rs2227981 with tumor risk.

Methods

Lots of databases included PubMed, Medline, Ovid Medline, EMBASE, Web of Knowledge were searched form 1990 to present. The main terms “programmed death-1”, “PD-1”, “polymorphism”, “cancer”, “tumor”, “carcinoma” in the title and/or abstract were used. References cited in the retrieved articles were also searched for relevant titles.

Data extraction and quality assessment

Two investigators independently reviewed all potentially eligible studies and collected data. The discussion and consensus were considered if the there were discrepancies. The quality of all collected data was ranked in accordance with the score of the non-randomized controlled clinical trial quality evaluation standard.

Statistical methods

The all collected data were included into Review Manager software (5.2.2). Heterogeneity was evaluated by Χ2 and I2. The dichotomous variables was analyzed via estimation of odds ratios (OR) with 95% confidence interval (95% CI). Heterogeneity was considered if the I2 statistic was >50% or P<0.05.

Results

Study characteristics

The characteristics of all included studies were summarized in Table 1. We collected the data from six studies [11-16], involving in a total of 1427 tumor patients and 1811 healthy control people. Two studies involved in colorectal cancer [14,16], of which one study involved in rectal cancer [14], one research involved in gastric cancer [15], two papers involved in breast cancer [12,13], and one article involved in gestational trophoblastic neoplasms [11]. Five studies were from Iran [11,13-16], only on from China [13]. More detail can be found in Table 1.

Table 1.

Charateristics of Studies Included in the Meta-analysis

Study Year Ethnicity Tumor type Case Control
CC CT TT CC+CT CC+TT CT+TT N CC CT TT CC+CT CC+TT CT+TT N
Dehaghani 2009 Iran gestational trophoblastic neoplasms 42 37 13 79 55 50 92 118 56 121 174 239 177 295
Haghshenas 2011 Iran breast cancer 194 191 50 385 244 241 443 137 145 46 282 183 191 328
Hua 2011 China breast cancer 295 169 22 464 317 191 490 244 210 24 454 268 234 512
Mojtahedi 2012a* Iran colon cancer 47 102 26 149 73 128 175 75 89 36 164 111 125 200
2012b* Rectal cancer 12 7 6 19 18 13 25 75 89 36 164 111 125 200
Savabkar 2013 Iran gastric cancer 50 66 6 116 56 72 122 89 70 7 159 96 77 166
Yousefi 2013 Iran Colorectal Cancer 18 27 35 45 53 62 80 43 45 22 88 65 67 110
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*

From the same study.

No association of PD-1 gene polymorphism with tumor risk

As shown in Figure 1, the meta analysis results shown that there was no association of PD-1 gene polymorphism with tumor risk under four genetic models. (CT+TT vs CC, OR=1.09, 95% CI=0.80-1.49, P=0.59; CT+CC vs TT, OR=0.93, 95% CI=0.52-1.66, P=0.61; TT vs CC, OR=0.99, 95% CI=0.57-1.72, P=0.97; CT vs CC, OR=1.16, 95% CI=0.80-1.70, P=0.43).

Figure 1.

Figure 1

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The meta analysis of PD-1 gene polymorphism with total tumor. A. CT+TT vs CC; B. CT+CC vs TT; C. TT vs CC; D. CT vs CC.

Sub-group analysis

We further explored potential causes of the PD-1 gene polymorphism with different tumors. As shown in Figure 2, there were a significantly difference on association of PD-1 gene polymorphism with digestive system tumor risk between tumor patients and healthy control people, except recessive model. (CT+TT vs CC, OR=1.57, 95% CI=1.20-2.07, P=0.001; TT vs CC, OR=1.67, 95% CI=1.12-2.49, P=0.01; CT vs CC, OR=1.51, 95% CI=1.13-2.01, P=0.005).

Figure 2.

Figure 2

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The meta analysis of PD-1 gene polymorphism with digestive system tumor. A. CT+TT vs CC; B. CT+CC vs TT; C. TT vs CC; D. CT vs CC.

For the tumor occurring only in women, the meta analysis results shown that there were association of PD-1 gene polymorphism with tumor risk under two models. (CT+TT vs CC, OR=0.80, 95% CI=0.67-0.95, P=0.01; TT vs CC, OR=0.61, 95% CI=0.44-0.83, P=0.002) However, the results under other two models indicated there were no correlation. (CT+CC vs TT, OR=0.57, 95% CI=0.26-1.25, P=0.16; CT vs CC, OR=0.99, 95% CI=0.61-1.62, P=0.98) (Figure 3).

Figure 3.

Figure 3

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The meta analysis of PD-1 gene polymorphism with tumor specific occurring in woman. A. CT+TT vs CC; B. CT+CC vs TT; C. TT vs CC; D. CT vs CC.

Discussion

In this meta analysis, the results shown that there were significantly difference on association of PD-1 rs2227981 gene polymorphism with special tumor type, including digestive system tumor and tumor occurring in woman under specific genetic models.

Human tumors have lots of genetic and epigenetic changes, which can produce some immune system-recognizing tumor antigens [17]. PD-1, liking CTLA-4, is a member of the B7-CD28 family and is potential therapeutic anticancer target based on its role of regulating T cell activation. PD-1 is a key immune-checkpoint receptor, which regulates immunosuppression by expression on activated T cell. Therefore, the PD-1 maybe a potential molecular target for tumor progression in tumors. The relative studies revealed that the association of CD28 and CTLA-4 gene polymorphisms with tumor risk is present [18-20]. Compared to the CTLA-4, the PD-1 is involve in the later of a T cell response in order to limit the T cell activity in the tumor microenvironment [21].

In our study, we demonstrated that PD-1 gene polymorphism rs2227981 is not relevant to total tumor types risk. So, we performed a sub-group analysis. The meta analysis results shown that an association of PD-1 gene polymorphism rs2227981 with digestive system tumors or tumors only occurring in woman under specific genetic models. Savabkar et al. [15] and Mojtahedi et al. [14] reported that significant association in CT genotype and gastric cancer and colon cancer risk. Similarly, other study demonstrated association of CT genotype of the PD-1 gene polymorphism and rheumatoid arthritis [22]. Moreover, PD-1 gene polymorphism CC genotype and C allele may play a potential risk in tumor specific occurring in woman, including breast cancer [13], which all are consistent with our results.

In here, five studies involved in Iran, only research is from China, which limited the meta analysis results. Moreover, other limitation in this meta analysis should be addressed. Firstly, a relatively small number of studies and sample size were included into this study, which may influence the statistical power of the analysis. Secondly, our meta analysis results were based on unadjusted estimates, while a more precise analysis could be conducted if individual data were available.

In conclusion, this study suggested that PD-1 gene polymorphism rs2227981 is associated with specific tumor types, including digestive system tumor and tumor specific occurring in woman. However, more studies needed to be included into this meta analysis.

Disclosure of conflict of interest

None.

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