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International Journal of Clinical and Experimental Medicine logoLink to International Journal of Clinical and Experimental Medicine
. 2015 Dec 15;8(12):22278–22285.

Programmed death-1 (PD-1) rs2227981 C > T polymorphism is associated with cancer susceptibility: a meta-analysis

Weifeng Tang 1,*, Yafeng Wang 2,*, Heping Jiang 3,*, Pinghua Liu 4, Chao Liu 5, Haiyong Gu 5, Shuchen Chen 1, Mingqiang Kang 1
PMCID: PMC4729990  PMID: 26885204

Abstract

Several studies have focused on the correlation between the programmed death-1 (PD-1) rs2227981 C > T polymorphism and the risk of cancer; however, the results of such studies remain conflicting. To address this gap, we performed this meta-analysis to identify the potential association. Search strategies were performed in PubMed and EMBASE using appropriate terms. In total, 2,977 cancer cases and 2,642 controls from seven publications were recruited in our study. According to the seven eligible publications, the odds ratios (ORs) and 95% confidence intervals (CIs) on the risk of cancer for the TT vs. CC and TT vs. CT+CC genotypes were 0.67 and 0.50-0.91 and 0.65 and 0.47-0.90, respectively. In a subgroup analysis by cancer type, PD-1 rs2227981 C > T polymorphism was associated with a significantly decreased risk of breast cancer (OR, 0.82; 95% CI, 0.71-0.95; P = 0.009 for T vs. C and OR, 0.76; 95% CI, 0.63-0.92; P = 0.005 for TT+CT vs. CC) and of other cancer (OR, 0.58; 95% CI, 0.36-0.92; P = 0.004 for TT vs. CT+CC). In a subgroup analysis by ethnicity, a significant decreased cancer risk was identified among Asians (OR, 0.74; 95% CI, 0.63-0.86; P < 0.001 for T vs. C and OR, 0.71; 95% CI, 0.59-0.87; P = 0.001 for TT+CT vs. CC) and among Caucasians (OR, 0.66; 95% CI, 0.44-0.99; P = 0.047 for TT vs. CT+CC). These findings highlight the fact that the T allele of PD-1 rs2227981 C > T polymorphism modestly decreases the susceptibility of cancer. Nevertheless, further large and well-designed studies are needed to enrich the evidence of this association.

Keywords: Polymorphism, programmed death-1, cancer risk

Introduction

It is estimated that about 14.1 million new cancer cases and 8.2 million cancer-associated deaths occurred in 2012 worldwide [1]. With new cases and mortality arising annually, cancer constitutes an enormous public health burden worldwide. These situations encourage researchers to explore the association of the latent environmental and genetic factors with the susceptibility of cancer. The aetiology of cancer is very elusive and has not been clarified thoroughly, although a number of investigations have focused on the function of the immune system [2,3]. Immune-related genetic mutations may also affect the risk of cancer [4,5].

Programmed death-1 (PD-1, also named CD279 or PDCD1), a co-inhibitory receptor that suppresses the activation of T lymphocytes and leads to peripheral immune tolerance, has been suggested to be involved in influencing the tumor cells to escape the host immune system after interaction with its two ligands, PD-1 ligand 1 (PD-L1) and PD-L2. PD-Ls are expressed in various malignancies [6-10]. In addition, up-regulation of PD-Ls in some cancers can contribute to tumor evasion and is associated with poor prognosis of malignancies [11-14]. Additionally, the function of regulatory T (Treg) cells also can be regulated through PD-1 pathway in cancer patients. Several recent investigations highlighted a correlation of PD-1 blockade with down-regulation of foxp3 expression by Treg cells in malignancy patients to correct immune escape [15-17].

The PD-1 gene lies in chromosome 2q37.3, encoding a 55 KDa type I transmembrane glycoprotein. Several researchers have reported single nucleotide polymorphisms (SNPs) within the PD-1 gene, such as rs36084323 A > G (PD-1.1), rs11568821 G > A (PD-1.3), rs2227981 C > T (PD-1.5), rs10204525 A > G (PD-1.6), rs7421861 T > C (PD-1.7), and rs2227982 C > T (PD-1.9) et al. Among these polymorphisms of the PD-1 gene, one of the most widely studied SNPs is rs2227981 C > T polymorphism with minor allele frequency (MAF) > 0.05. This very SNP is located in exon 5 and does not affect the final amino acid residue (a synonymous mutation; Ala to Ala). To date, a few studies have explored the correlation of PD-1 rs2227981 C > T polymorphism with caner susceptibility [18-24]; however, the results were conflicting. Thus, we performed this meta-analysis by pooling data from eligible case-control studies to further clarify the role of the PD-1 rs2227981 C > T polymorphism in cancer.

Materials and methods

Search strategy

PubMed and EMBASE databases were used to search the potential papers which were published before March 4, 2015 without any language restriction. The following terms were used: ‘polymorphism’ or ‘variant’ or ‘SNP’ and ‘programmed death-1’, ‘PD-1’ or ‘PDCD1’ and ‘cancer’ or ‘carcinoma’ or ‘malignance’.

Inclusion criteria and exclusion criteria

The major criteria were used to include eligible studies: (a) case-control studies; (b) studies that provided sufficient data to calculate crude odds ratios (ORs) and 95% confidence intervals (CIs) and (c) those assessing the correlation between the PD-1 rs2227981 C > T polymorphism and the risk of cancer. The major excluded criteria were: (1) case reports, system reviews, editorials, letters, and comments; (2) not case-control study and (3) duplicated publications.

Data extraction

Two reviewers (W. Tang and Y. Wang) screened and extracted data independently. If there were any discrepancies, differences were adjudicated through discussions between all reviewers. The following information was extracted from every study: PD-1 rs2227981 C > T polymorphism information, first author’s surname, year of publication, country, ethnicity and sample size.

Statistical analysis

Hardy-Weinberg equilibrium (HWE) in the controls for individual study was assessed using an internet-based HWE programme (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl) and violation of HWE was defined by P < 0.05. Correlation between PD-1 rs2227981 C > T polymorphism and cancer susceptibility was assessed using crude ORs together with corresponding 95% CIs. The Q-statistic and I2 statistical tests were harnessed to measure the heterogeneity among studies. If the value of I2 > 50% or P < 0.10 suggests substantial heterogeneity, random-effects models using DerSimonian-Laird method were used [25], otherwise, fixed-effects models using Mantel-Haenszel methods was performed [26]. The Begg’s funnel plot [27] and Egger’s linear regression [28] were used to assessed the potential publication bias. One-way sensitivity analysis was harnessed to assess the stability of our results. All analyses were conducted by the Stata 12.0 statistical software (Stata Corp LP, College Station, TX, USA). A P < 0.05 (two-sided) was defined as a statistically significant difference.

Results

Study characteristics

According to the search keywords and subject terms from the databases of PubMed and EMBASE, one hundred and eighty-eight potential correlated publications were enrolled. Based on the included criteria, seven studies were identified [18-24] (Figure 1). Among them, two case-control studies deviated from HWE [18,19]. Five case-control studies focused on Caucasians [19,20,22-24], two focused on Asias [18,21]. Of these articles, two investigated breast cancer [20,21], the others investigated lung cancer [18], colorectal cancer [22], gastric cancer [23], gestational trophoblastic neoplasm [19] and cervical cancer [24]. Characteristics from each included study were listed in Table 1. The genotype numbers and P value of HWE for the eligible studies were summarized in Table 2.

Figure 1.

Figure 1

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Flow diagram of articles selection process for metaanalysis.

Table 1.

Characteristics of the individual studies included in the meta-analysis

Study Year Country Ethnicity Cancer type Case/control Genotype method
Yin et al. [18] 2014 China Asians Lung cancer 324/330 PCR-RFLP
Savabkar et al. [23] 2013 Iran Caucasians Gastric cancer 122/166 PCR-RFLP
Mojtahedi et al. [22] 2012 Iran Caucasians Colorectal cancer 200/200 PCR-RFLP
Haghshenas et al. [20]% 2011 Iran Caucasians Breast cancer 443/328 PCR-RFLP
Hua et al. [21] 2011 China Asians Breast cancer 490/512 PCR-RFLP
Ivansson et al. [24] 2010 Sweden Caucasians Cervical cancer 1306/811 TaqMan
Dehaghani et al. [19] 2009 Iran Caucasians Gestational trophoblastic neoplasm 92/295 PCR-RFLP
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PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism.

Table 2.

Distribution of PD-1 rs2227981 C > T polymorphism genotype and allele

Study Year Case Control Case Control HWE
CC CT TT CC CT TT T C T C
Yin et al. [18] 2014 198 106 20 181 105 44 146 502 193 467 No
Savabkar et al. [23] 2013 50 66 6 89 70 7 78 166 84 248 Yes
Mojtahedi et al. [22] 2012 59 109 32 75 89 36 173 227 161 239 Yes
Haghshenas et al. [20] 2011 194 191 50 137 145 46 291 579 237 419 Yes
Hua et al. [21] 2011 295 169 22 244 210 24 213 759 258 698 Yes
Ivansson et al. [24] 2010 471 603 226 257 375 178 1055 1545 731 889 Yes
Dehaghani et al. [19] 2009 42 37 13 118 56 121 63 121 298 292 No
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Quantitative synthesis

A total of 2,977 cancer cases and 2,642 controls from seven eligible investigations were enrolled. Our findings highlighted the statistical evidence of association between PD-1 rs2227981 C > T variants and a decreased risk of malignance in two genetic models: TT vs. CC (OR, 0.67; 95% CI, 0.50-0.91; P = 0.011) and TT vs. CT+CC (OR, 0.65; 95% CI, 0.47-0.90; P = 0.009) (Table 3 and Figure 2). In a subgroup analysis by cancer type, PD-1 rs2227981 C > T polymorphism was associated with a significantly decreased risk of breast cancer (OR, 0.82; 95% CI, 0.71-0.95; P = 0.009 for T vs. C and OR, 0.76; 95% CI, 0.63-0.92; P = 0.005 for TT+CT vs. CC) and of other cancer (OR, 0.58; 95% CI, 0.36-0.92; P = 0.004 for TT vs. CT+CC). In a subgroup analysis by ethnicity, a significant decreased cancer risk was identified among Asians (OR, 0.74; 95% CI, 0.63-0.86; P < 0.001 for T vs. C and OR, 0.71; 95% CI, 0.59-0.87; P = 0.001 for TT+CT vs. CC) and among Caucasians (OR, 0.66; 95% CI, 0.44-0.99; P = 0.047 for TT vs. CT+CC).

Table 3.

Meta-analysis of the PD-1 rs2227981 C > T polymorphism and cancer risk

No. of study T vs. C TT vs. CC TT+CT vs. CC TT vs. CT+CC
OR (95% CI) P P (Q-test) OR (95% CI) P P (Q-test) OR (95% CI) P P (Q-test) OR (95% CI) P P (Q-test)
Total 7 0.84 (0.71-1.00) 0.050 0.001 0.67 (0.50-0.91) 0.011 0.032 0.91 (0.74-1.12) 0.381 0.007 0.65 (0.47-0.90) 0.009 0.008
Ethnicity
    Asians 2 0.74 (0.63-0.86) < 0.001 0.647 0.56 (0.31-1.00) 0.051 0.154 0.71 (0.59-0.87) 0.001 0.510 0.61 (0.30-1.27) 0.188 0.073
    Caucasians 5 0.90 (0.71-1.14) 0.367 0.001 0.73 (0.49-1.07) 0.101 0.032 1.03 (0.79-1.34) 0.843 0.015 0.66 (0.44-0.99) 0.047 0.009
Cancer type
    Breast cancer 2 0.82 (0.71-0.95) 0.009 0.301 0.76 (0.53-1.10) 0.147 0.975 0.76 (0.63-0.92) 0.005 0.159 0.83 (0.59-1.17) 0.292 0.750
    Other cancer 5 0.85 (0.66-1.11) 0.238 < 0.001 0.64 (0.41-1.01) 0.056 0.010 1.00 (0.75-1.33) 0.994 0.009 0.58 (0.36-0.92) 0.022 0.003
HWE
    Yes 5 0.93 (0.79-1.10) 0.400 0.019 0.77 (0.63-0.93) 0.006 0.446 0.98 (0.74-1.29) 0.871 0.002 0.79 (0.66-0.94) 0.007 0.905
    No 2 0.61 (0.45-0.84) 0.002 0.138 0.36 (0.24-0.56) < 0.001 0.476 0.78 (0.60-1.01) 0.060 0.927 0.32 (0.21-0.49) < 0.001 0.165
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HWE: Hardy-Weinberg equilibrium. Bold values are statistically significant (P < 0.05).

Figure 2.

Figure 2

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Meta-analysis with a fixed-effects model for the association between PD-1 rs2227981 C > T polymorphism and cancer risk (TT vs. CT+CC genetic model).

Publication bias

Begg’s funnel plots and Egger’s linear regression tests were harnessed to assess the publication bias (Figure 3). Significant publication bias was found in some genetic models (T vs. C: Begg’s test P = 0.764, Egger’s test P = 0.828; TT vs. CC: Begg’s test P = 1.000, Egger’s test P = 0.969; TT+CT vs. CC: Begg’s test P = 0.133, Egger’s test P = 0.148; TT vs. CT+CC: Begg’s test P = 0.548, Egger’s test P = 0.624).

Figure 3.

Figure 3

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Begg’s funnel plot of meta-analysis of the association between PD-1 rs2227981 C > T polymorphism and the risk of cancer (TT vs. CC genetic model).

Sensitivity analyses

Sensitivity analysis was conducted to assess the influence of anyone study on the pooled ORs and CIs by omitting an individual study in turn. Our findings showed that these results were robust and reliable (Figure 4) (data not shown).

Figure 4.

Figure 4

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Sensitivity analysis of the influence of TT vs. CC compare genetic model (random-effects estimates for PD-1 rs2227981 C > T polymorphism).

Heterogeneity

As shown in Table 3, heterogeneity across the studies was significant in the current study. Thus, we assessed the sources of heterogeneity by race, the origin of cancer cells and HWE (Table 3). The findings showed that Caucasians and other cancer may contribute to the major sources of heterogeneity.

Discussion

In total, 2,977 cancer cases and 2,642 controls from seven eligible publications were recruited to investigate the correlation between the PD-1 rs2227981 C > T polymorphism and the risk of cancer.

According to the results, the PD-1 rs2227981 C > T polymorphism was suggested to be associated with a significantly decreased risk of cancer. The TT homozygote carriers suggested lower cancer incident susceptibility in comparison with the CC and CC+CT genotype carriers. The crude ORs and 95% CIs were 0.67 and 0.50-0.91, and 0.65 and 0.47-0.90, respectively. Although no statistical correlation between the PD-1 rs2227981 C > T polymorphism and the risk of cancer was identified, when the genetic comparisons were carried out between the TT+CT and CC homozygotes or between the T and C alleles, there remained a latent effect from the TT+CT genotypes or the T allele on the susceptibility of cancer. The crude ORs and 95% CIs were 0.91 and 0.74-1.12, respectively, for the TT+CT versus the CC homozygotes and 0.84 and 0.71-1.00, respectively, for the T versus C alleles.

The findings of this pooled study were supported by some investigations. In a previous study in China conducted by Hua et al [21], compared with the C allele, the T allele was a protective factor of breast cancer. Our findings were also supported by a Sweden study [24]. In this study (1, 306 cervical cancer cases and 811 controls), the TT homozygote reduced the risk of cervical cancer significantly. The ORs and 95% CIs were 0.69 and 0.54-0.89, respectively, for TT vs. CC and 0.75 and 0.60-0.93, respectively, for TT vs. CC+CT. The majority of our findings demonstrated the protective effect from the T allele on the susceptibility of cancer. In the future, further investigations based on a larger population and detailed gene-environment data are needed to be undertaken to confirm or refute our findings.

In the current study, two studies deviated from the HWE in controls, which showed the presence of population stratification and/or genotyping errors [18,19]. When we omitted these two studies, the correlation between PD-1 rs2227981 C > T polymorphism and cancer risk was also significant with respect to the two genetic models (OR, 0.77; 95% CI, 0.63-0.93; P = 0.006 for TT vs. CC and OR, 0.79; 95% CI, 0.66-0.94; P = 0.007 for TT vs. CT+CC; Table 3), attesting the robustness of our findings.

Several limitations of our study should be addressed when interpreting these findings. Due to the limited number of publications recruited in this pooled study, these findings should be interpreted with very caution. In addition, there were only two case-control studies conducted in Asians, which may generate a fluctuated assessment or restrict the statistical power to detect a real influence. Moreover, in this meta-analysis, large heterogeneities across the studies included in the current analysis should also be taken into consideration. Finally, in this study, we only focused on PD-1 rs2227981 C > T polymorphism, and did not ponder other PD-1 polymorphisms or risk genes. However, our study also had several merits. First, to date, this is the first meta-analysis detecting the association of PD-1 rs2227981 C > T polymorphism with the risk of cancer. The results demonstrated that this polymorphism was associated with the decreased risk of cancer. Second, although the large heterogeneities were identified in our study, the results of sensitivity analysis attesting the robustness of our findings.

In conclusion, our findings suggest that the T allele modestly decrease the susceptibility of cancer. Nevertheless, for practical reasons, further evidence from epidemiological studies across different populations incorporating with the functional assessments is required in order to confirm or refute the findings of this study.

Acknowledgements

This study was supported in part by National Natural Science Foundation of China (81472332, 81341006), Fujian Province Natural Science Foundation (2013J01126, 2013J05116), Fujian Medical University professor fund (JS12008), The Fund of Union Hospital (2015TC-1-048 and 2015TC-2-004), Fujian Province Science and Technology Programmed Fund (2012Y0030), Fujian Medical Innovation Fund (2014-CX-15) and Jiangsu University Clinical Medicine Science and Technology Development Fund (JLY20140012).

Disclosure of conflict of interest

None.

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