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. 2019 Aug 10;11(8):1150. doi: 10.3390/cancers11081150

Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies

Mohammad Hashemi 1,2,*, Shima Karami 2, Sahel Sarabandi 2, Abdolkarim Moazeni-Roodi 3, Andrzej Małecki 4, Saeid Ghavami 5,6,*, Emilia Wiechec 7,*
PMCID: PMC6721817  PMID: 31405171

Abstract

A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis study to identify the impact of PD-1 and PD-L1 polymorphisms on overall cancer susceptibility. The findings revealed that PD-1 rs2227981 and rs11568821 polymorphisms significantly decreased the overall cancer risk (Odds Ratio (OR) = 0.82, 95% CI = 0.68–0.99, p = 0.04, TT vs. CT+CC; OR = 0.79, 95% CI = 0.67–0.94, p = 0.006, AG vs. GG, and OR = 0.82, 95% CI = 0.70–0.96, p = 0.020, AG+AA vs. GG, respectively), while PD-1 rs7421861 polymorphism significantly increased the risk of developing cancer (OR = 1.16, 95% CI = 1.02–1.33, p = 0.03, CT vs. TT). The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41–0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50–0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60–0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63–0.96, p = 0.02) genetic models. No significant association between rs2227982, rs36084323, rs10204525, and rs2890658 polymorphisms and overall cancer risk has been found. In conclusions, the results of this meta-analysis have revealed an association between PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms and overall cancer susceptibility.

Keywords: apoptosis, PD-1, PD-L1, polymorphism, cancer, meta-analysis

1. Introduction

Cancer, a main public health issue is the leading cause of death globally. It was estimated that there will be about 18.1 million new cases of cancer and 9.6 million cancer deaths in 2018 [1]. Thus, the etiology and pathogenesis of cancer has not been elucidated completely and their understanding is decisive. Genome-wide association studies (GWAS) have simplified the search for potential genetic variants that are implicated in many diseases including cancer and single nucleotide polymorphisms (SNPs) are well studied genetic variations found in human genome. The number of SNPs that have so far been identified to play an important role in cancer susceptibility is significant [2]. It has been proposed that the immune system plays a key role in resisting and eliminating cancer cells and can affect cancer susceptibility. One of the main hallmarks of cancer cells is the immune suppression and evasion [3].

Tumor cells express the programmed death-1-ligand 1 (PD-L1) as an adaptive, resistant mechanism to suppress the inhibitory receptor, namely programmed cell death-1 (PD-1) in order to evade host immunosurveillance [4]. PD-1, also known as PD1 and CD279, is a cell surface immunosuppressive receptor belonging to immunoglobulin superfamily and is encoded by the PDCD1 gene [5,6,7]. PD-1, is a negative regulator of the immune system and is expressed on CD4+ T cells, CD8+ T cells, NKT cells, B cells, and monocytes [8,9]. The antitumor CD8+ T cells exhibit preferential expression of PD-1 leading to their exhaustion and functional impairment, which in turns lead to attenuated tumor-specific immunity disseminating tumor progression [10,11]. The PD-1 blockade elevates the magnitude of T cell response such as proliferation of T cells and production of effector cytokines [12]. Additionally, PD-L1 signaling through conserved sequence motifs confers resistance of cancer cells towards proapoptotic interferon (IFN)-mediated cytotoxicity [13].

PD-1/PD-L1 axis is an important pathway to maintain immune tolerance and prevent autoimmune diseases in the evolution of immunity [14,15,16]. Furthermore, it influences the balance between tumor immune surveillance and immune resistance [17,18]. Elevated PD-L1 expression in tumor cells or tumor-infiltrating lymphocytes (TILs) leads to the exhaustion of T cells [19], and hence attenuated tumor-specific immunity disseminating tumor progression [20]. Gene polymorphisms might affect the normal process of gene activation and transcriptional initiation, hence influence the quantity of mRNA and encoded protein [21]. Both PD-1 and PD-L1 are polymorphic. Several studies investigated the association between genetic polymorphisms of PD-1 and PD-L1 genes and the risk of various cancers, but the finding are still inconclusive [5,6,7,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. Thus, we performed a comprehensive meta-analysis in order to study the association of polymorphisms in PD-1 (rs2227981, rs2227982, rs11568821, rs7421861, rs36084323, and rs10204525) and PD-L1 (rs4143815, and rs2890658) with the risk of cancer. The locations and base pair positions of single nucleotide polymorphisms (SNPs) in PD-1 and PD-L1 genes are presented in Table 1.

Table 1.

Locations and base pair positions of single nucleotide polymorphisms (SNPs) in PD-1 and PD-L1 genes.

Gene Name db SNP rs # ID a Chromosome Position Location Base Change Amino Acid Change
PD-1 rs2227981 chr2:241851121 Upstream C/T -
rs2227982 chr2:241851281 Exon C/T Ala215Val
rs7421861 chr2:241853198 Intron T/C -
rs11568821 chr2:241851760 Intron G/A -
rs36084323 chr2:241859444 Upstream G/A -
rs10204525 chr2:241850169 3′UTR A/G -
PD-L1 rs4143815 chr9:5468257 3′UTR G/C -
rs2890658 chr9:5465130 Intron A/C -
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a db = databases; rs # = reference SNP #; UTR: untranslated region.

2. Results

2.1. Study Characteristics

A flow diagram of the study selection process is shown in Figure 1. For PD-1 polymorphisms, 54 case-control studies from a total of 26 articles [5,6,7,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,52] examining the associations of 6 widely studied polymorphisms in PD-1 gene and cancer risk were included in this meta-analysis. There were 16 studies involving 5622 cases and 5450 controls that reported the association between PD-1 rs2227981 polymorphism and cancer. Eleven studies including 4766 cases and 5839 controls investigated the relationship between PD-1 rs2227982 polymorphism and cancer. Nine studies with 1846 cases and 1907 cases reported the association between PD-1 rs11568821 variant and cancer risk. Seven studies including 3576 cancer cases and 5277 controls studied the correlation between PD-1 rs7421861 polymorphism and cancer. Seven studies involving 3589 cases and 4314 controls examined the association between PD-1 rs36084323 polymorphism and cancer risk. Six studies including 3366 cancer cases and 4391 controls studied the relationship between PD-1 rs10204525 polymorphism and cancer.

Figure 1.

Figure 1

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Flow diagram of study selection for this meta-analysis.

For PD-L1 polymorphisms, 13 case-control studies from 10 articles [27,38,44,45,46,47,48,49,50,51] that assessed the impact of two polymorphisms of PD-L1 were included in the pooled analysis. Eight studies including 3030 cases and 4145 controls evaluated the association between PD-L1 rs4143815 polymorphism and cancer risk. Five studies with 1909 cases and 1970 controls assessed the correlation between PD-L1 rs2890658 variant and cancer risk. The characteristics of all these studies are shown in Table 2.

Table 2.

Characteristics of the studies eligible for meta-analysis.

First Author Year Country Ethnicity Cancer Type Source of Control Genotyping Method Case/Control Cases Controls HWE
PD-1 rs2227981 CC CT TT C T CC CT TT C T
Fathi 2019 Iran Asian Squamous Cell Carcinomas of Head and Neck HB PCR-RFLP 150/150 65 69 16 199 101 66 71 13 203 97 0.317
Gomez 2018 Brazil South American Cutaneous Melanoma PB RT-PCR 250/250 87 126 37 300 200 85 130 35 300 200 0.188
Haghshenas 2011 Iran Asian Breast cancer PB PCR-RFLP 435/328 194 191 50 579 291 137 145 46 419 237 0.446
Haghshenas 2017 Iran Asian Thyroid cancer PB PCR-RFLP 105/160 40 51 14 131 79 99 51 10 249 71 0.331
Hua 2011 China Asian breast cancer PB PCR-RFLP 486/478 295 169 22 759 213 244 210 24 698 258 0.012
Ivansson 2010 Sweden Caucasian Cervical cancer PB TaqMan 1300/810 471 603 226 1545 1055 257 375 178 889 731 0.064
Li 2016 China Asian Cervical cancer PB PCR-RFLP 256/250 45 167 44 257 255 62 101 87 225 275 0.004
Li 2017 China Asian Ovarian cancer HB PCR-LDR 620/620 351 233 36 935 305 319 250 51 888 352 0.837
Ma 2015 China Asian lung cancer PB PCR-RFLP 528/600 244 216 68 704 352 256 246 98 758 442 0.004
Mojtahedi 2012 Iran Asian Colon cancer PB PCR-RFLP 175/200 47 102 26 196 154 75 89 36 239 161 0.290
Mojtahedi 2012 Iran Asian Rectal cancer PB PCR-RFLP 25/200 12 7 6 31 19 75 89 36 239 161 0.290
Namavar Jahromi 2017 Iran Asian Malignant Brain tumor PB PCR-RFLP 56/150 22 31 3 75 37 94 47 9 235 65 0.346
Pirdelkhosh 2018 Iran Asian NSCLC PB PCR-RFLP 206/173 78 100 28 256 156 60 89 24 209 137 0.321
Savabkar 2013 Iran Asian Gastric cancer HB PCR-RFLP 122/166 50 66 6 166 78 89 70 7 248 84 0.136
Yin 2014 China Asian Lung cancer PB PCR 324/330 198 106 20 502 146 181 105 44 467 193 0.001
Zhou 2016 China Asian ESCC PB PCR-LDR 584/585 291 241 52 823 345 310 229 46 849 321 0.683
PD-1 rs2227982 CC CT TT C T CC CT TT C T
Fathi 2019 Iran Asian Squamous Cell Carcinomas of Head and Neck HB PCR-RFLP 150/150 146 4 0 296 4 146 4 0 296 4 0.868
Gomez 2018 Brazil South American Cutaneous Melanoma PB RT-PCR 250/250 227 21 2 475 25 225 25 0 475 25 0.405
Hua 2011 China Asian breast cancer PB PCR-RFLP 487/506 111 249 127 471 503 95 268 143 458 554 0.121
Ma 2015 China Asian lung cancer PB PCR-RFLP 528/600 343 148 37 834 222 404 168 28 976 224 0.056
Qiu 2014 China Asian esophageal cancer HB PCR-LDR 616/681 159 303 154 621 611 189 325 167 703 659 0.245
Ramzi 2018 Iran Asian Leukemia PB PCR-RFLP 59/38 38 18 3 94 24 17 19 2 53 23 0.255
Ren 2016 China Asian Breast Cancer PB MassARRAY 557/582 172 257 128 601 513 137 299 146 573 591 0.503
Tan 2018 China Asian Ovarian cancer PB PCR-RFLP 164/170 87 60 17 234 94 111 48 11 270 70 0.075
Tang 2015 China Asian Gastric cardia adenocarcinoma HB PCR-LDR 330/603 75 168 87 318 342 163 292 148 618 588 0.448
Tang 2017 China Asian Esophagogastric junction adenocarcinoma HB SNPscan 1041/1674 220 549 272 989 1093 416 816 442 1648 1700 0.309
Zhou 2016 China Asian ESCC PB PCR-LDR 584/585 149 305 130 603 565 150 297 138 597 573 0.702
PD-1 rs7421861 TT TC CC T C TT TC CC T C
Ge 2015 China Asian Colon cancer HB PCR-RFLP 199/620 133 60 6 326 72 440 163 17 1043 197 0.685
Ge 2015 China Asian Rectal cancer HB PCR-RFLP 362/620 241 114 7 596 128 440 163 17 1043 197 0.685
Hua 2011 China Asian Breast cancer PB PCR-RFLP 490/512 333 146 11 812 168 370 130 12 870 154 0.885
Qiu 2014 China Asian esophageal cancer HB PCR-LDR 600/673 411 168 21 990 210 460 188 25 1108 238 0.295
Ren 2016 China Asian Breast Cancer PB MassARRAY 560/580 341 196 23 878 242 347 205 28 899 261 0.746
Tang 2015 China Asian Gastric cardia adenocarcinoma HB PCR-LDR 324/598 226 91 7 543 105 408 168 22 984 212 0.368
Tang 2017 China Asian esophagogastric junction adenocarcinoma HB SNPscan 1041/1674 642 358 41 1642 440 1166 454 54 2786 562 0.232
PD-1 rs11568821 GG AG AA G A GG AG AA G A
Bayram 2012 Turkey Asian liver cancer HB PCR-RFLP 236/236 191 45 0 427 45 180 56 0 416 56 0.039
Fathi 2019 Iran Asian Squamous Cell Carcinomas of Head and Neck HB PCR-RFLP 150/150 119 27 4 265 35 113 32 5 258 42 0.162
Haghshenas 2011 Iran Asian Breast cancer PB PCR-RFLP 436/290 365 63 8 793 79 231 55 4 517 63 0.726
Haghshenas 2017 Iran Asian Thyroid cancer PB PCR-RFLP 95/160 82 13 0 177 13 127 30 3 284 36 0.440
Ma 2015 China Asian lung cancer PB PCR-RFLP 528/600 426 102 0 954 102 456 142 2 1054 146 0.009
Namavar Jahromi 2017 Iran Asian Malignant Brain tumor PB PCR-RFLP 56/150 47 8 1 102 10 116 30 4 262 38 0.240
Pirdelkhosh 2018 Iran Asian NSCLC PB PCR-RFLP 206/173 171 31 4 373 39 144 26 3 314 32 0.168
Ramzi 2018 Iran Asian Leukemia PB PCR-RFLP 59/38 38 18 3 94 24 21 13 4 55 21 0.373
Yousefi 2013 Asian colon cancer PB 80/110 18 27 35 63 97 43 45 22 131 89 0.114
PD-1 rs36084323 GG AG AA G A GG AG AA G A
Gomez 2018 Brazil South American Cutaneous Melanoma PB RT-PCR 250/250 226 18 6 470 30 225 25 0 475 25 0.405
Hua 2011 China Asian Breast cancer PB PCR-RFLP 490/512 103 271 116 477 503 140 260 112 540 484 0.673
Li 2017 China Asian Ovarian cancer HB PCR-LDR 620/620 150 301 169 601 639 168 323 129 659 581 0.251
Ma 2015 China Asian lung cancer PB PCR-RFLP 528/600 144 246 138 534 522 156 296 148 608 592 0.747
Shamsdin 2018 Iran Asian Colon cancer PB PCR-RFLP 76/73 60 15 1 135 17 18 28 27 64 82 0.059
Tang 2017 China Asian esophagogastric junction adenocarcinoma HB SNPscan 1041/1674 238 521 282 997 1085 430 800 444 1660 1688 0.071
Zhou 2016 China Asian ESCC PB PCR-LDR 584/585 147 303 134 597 571 145 298 142 588 582 0.649
PD-1 rs10204525 AA AG GG A G AA AG GG A G
Li 2013 China Asian HCC PB TIANamp 271/318 180 83 8 443 99 160 130 28 450 186 0.828
Qiu 2014 China Asian esophageal cancer HB PCR-LDR 600/651 317 240 43 874 326 345 243 63 933 369 0.039
Ren 2016 China Asian Breast Cancer PB MassARRAY 559/582 257 248 54 762 356 291 240 51 822 342 0.880
Tang 2015 China Asian Gastric cardia adenocarcinoma HB PCR-LDR 313/581 169 123 21 461 165 309 219 53 837 325 0.120
Tang 2017 China Asian esophagogastric junction adenocarcinoma HB SNPscan 1039/1674 544 397 98 1485 593 870 672 132 2412 936 0.888
Zhou 2016 China Asian ESCC PB PCR-LDR 584/585 325 226 33 876 292 296 238 51 830 340 0.749
PD-L1 rs4143815 GG CG CC G C GG CG CC G C
Catalano 2018 Czech Caucasian Colon cancer HB TaqMan 824/1103 388 345 91 1121 527 514 467 122 1495 711 0.306
Catalano 2018 Czech Caucasian Rectal cancer HB TaqMan 371/1103 167 162 42 496 246 514 467 122 1495 711 0.306
Du 2017 China Asian NSCLC HB sequencing 320/199 52 145 123 249 391 40 80 79 160 238 0.021
Tan 2018 China Asian Ovarian cancer PB PCR-RFLP 164/170 51 82 31 184 144 38 78 54 154 186 0.334
Tao 2017 China Asian Gastric cancer HB Sequencing 346/500 123 153 70 399 293 117 223 160 457 543 0.023
Wang 2013 China Asian Gastric cancer HB sequencing 205/393 88 72 45 248 162 70 188 135 328 458 0.746
Xie 2018 China Asian HCC HB sequencing 225/200 74 101 50 249 201 31 104 65 166 234 0.316
Zhou 2017 China Asian ESCC PB PCR-LDR 575/577 87 277 211 451 699 85 289 203 459 695 0.275
PD-L1 rs2890658 AA AC CC A C AA AC CC A C
Chen 2014 China Asian NSCLC HB PCR-RFLP 293/293 242 48 3 532 54 266 26 1 558 28 0.671
Cheng 2015 China Asian NSCLC HB PCR-RFLP 288/300 233 51 4 517 59 269 30 1 568 32 0.867
Ma 2015 China Asian lung cancer PB PCR-RFLP 528/600 416 106 6 938 118 512 84 4 1108 92 0.785
Xie 2018 China Asian HCC HB sequencing 225/200 170 49 6 389 61 139 55 6 333 67 0.844
Zhou 2017 China Asian ESCC PB PCR-LDR 575/577 18 161 396 197 953 15 144 418 174 980 0.541
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List of Abbreviations: HCC: Hepatocellular carcinoma; PB: Population-based; HB: Hospital-based; ESCC: Esophageal squamous cell carcinoma; LDR: Ligase Detection Reaction; NSCLC: non-small cell lung cancer; PCR-RFLP: PCR-Restriction fragment length polymorphism; HWE: Hardy-Weinberg equilibrium; MassARRAY®System: Nonfluorescent detection platform utilizing mass spectrometry to accurately measure PCR-derived amplicons.

2.2. Main Analysis Results

2.2.1. Association of PD-1 Polymorphisms with Cancer Risk

The pooled analysis involving PD-1 rs2227981 polymorphism revealed that this variant significantly decreased the overall cancer risk in recessive (OR = 0.82, 95% CI = 0.68–0.99, p = 0.04, TT vs. CT+CC) genetic models (Table 3 and Figure 2).

Table 3.

The pooled ORs and 95% CIs for the association between PD-1 and PD-L1 polymorphisms and cancer susceptibility.

Polymorphism n Genetic Model Association Test Heterogeneity Test Publication Bias Test
OR (95% CI) Z p χ2 I2 (%) p Egger’s Test p Begg’s Test p
PD-1 rs2227981 16 CT vs. CC 1.11 (0.93–1.33) 1.16 0.25 61.22 75 <0.00001 0.032 0.031
TT vs. CC 0.86 (0.72–1.04) 1.51 0.13 27.39 45 0.03 0.034 0.024
CT+TT vs. CC 1.05 (0.89–1.24) 0.64 0.52 58.58 74 <0.00001 0.019 0.005
TT vs. CT+CC 0.82 (0.68–0.99) 2.04 0.04 31.12 52 0.008 0.155 0.150
T vs. C 0.98 (0.87–1.09) 0.43 0.66 51.48 71 <0.00001 0.020 0.012
PD-1 rs2227982 11 CT vs. CC 1.01 (0.85–1.19) 0.09 0.930 24.53 59 0.006 0.359 0.186
TT vs. CC 1.05 (0.87–1.26) 0.51 0.611 17.10 47 0.050 0.288 0.180
CT+TT vs. CC 1.02 (0.86–1.20) 0.22 0.829 26.49 62 0.003 0.469 0.484
TT vs. CT+CC 1.00 (0.90–1.10) 0.04 0.97 7.52 0 0.581 0.184 0.211
T vs. C 1.02 (0.92–1.12) 0.38 0.707 20.50 51 0.025 0.927 0.715
PD-1 rs11568821 9 AG vs. GG 0.79 (0.67–0.94) 2.73 0.006 3.89 0 0.87 0.499 0.409
AA vs. GG 1.01 (0.47–2.14) 0.01 0.99 13.19 47 0.07 0.015 0.091
AG+AA vs. GG 0.82 (0.70–0.96) 2.42 0.020 11.30 29 0.19 0.613 0.835
AA vs. AG+GG 1.07 (0.54–2.13) 0.19 0.846 11.79 41 0.11 0.010 0.095
A vs. G 0.88 (0.68–1.15) 0.92 0.36 24.39 67 0.002 0.822 0.835
PD-1 rs7421861 7 CT vs. TT 1.16 (1.02–1.33) 2.20 0.03 0.01 46 0.09 0.215 0.881
CC vs. TT 1.00 (0.79–1.28) 0.03 0.98 4.76 0 0.57 0.116 0.881
CT+CC vs. TT 1.14 (0.99–1.31) 1.81 0.07 12.93 54 0.04 0.196 0.453
CC vs. CT+TT 0.96 (0.75–1.22) 0.37 0.71 3.49 0 0.75 0.101 0.652
C vs. T 1.09 (0.97–1.23) 1.42 0.16 13.02 54 0.04 0.200 0.652
PD-1 rs36084323 7 AG vs. GG 0.92 (0.71–1.20) 0.60 0.55 27.83 78 0.0001 0.042 0.051
AA vs. GG 1.08 (0.77–1.52) 0.45 0.66 28.21 79 0.0001 0.079 0.188
AG+AA vs. GG 0.88 (0.64–1.21) 0.79 0.43 47.46 87 <0.00001 0.081 0.293
AA vs. AG+GG 1.06 (0.83–1.36) 0.46 0.64 22.86 74 0.0008 0.137 0.348
A vs. G 0.89 (0.70–1.14) 0.92 0.36 66.01 91 <0.00001 0.160 0.453
PD-1 rs10204525 6 AG vs. AA 0.94 (0.80–1.10) 0.76 0.45 13.13 62 0.02 0.640 0.851
GG vs. AA 0.76 (0.53–1.09) 1.48 0.14 19.40 74 0.002 0.031 0.091
AG+GG vs. AA 0.90 (0.75–1.08) 1.10 0.27 18.41 73 0.002 0.399 0.188
GG vs. AG+AA 0.78 (0.57–1.09) 1.46 0.14 16.64 70 0.005 0.020 0.039
G vs. A 0.89 (0.76–1.05) 1.38 0.17 23.71 79 0.0002 0.172 0.091
PD-L1 rs4143815 8 CG vs. GG 0.75 (0.55–1.01) 1.89 0.06 43.76 84 <0.0001 0.230 0.322
CC vs. GG 0.62 (0.41–0.94) 2.28 0.02 52.19 87 <0.00001 0.188 0.138
CG+CC vs. GG 0.70 (0.50–0.97) 2.15 0.03 43.20 84 <0.00001 0.184 0.138
CC vs. CG+GG 0.76 (0.60–0.96) 2.30 0.02 25.19 72 0.0007 0.070 0.138
C vs. G 0.78 (0.63–0.96) 2.33 0.02 61.68 89 <0.00001 0.100 0.138
PD-L1 rs2890658 5 AC vs. AA 1.36 (0.92–2.01) 1.53 0.13 13.83 71 0.008 0.757 0.624
CC vs. AA 1.12 (0.68–1.84) 0.45 0.65 4.31 7 0.37 0.032 0.050
AC+CC vs. AA 1.35 (0.89–2.04) 1.43 0.15 16.24 75 0.003 0.736 1.000
CC vs. AC+AA 0.90 (0.71–1.15) 0.83 0.41 4.25 6 0.37 0.041 0.050
C vs. A 1.30 (0.88–1.91) 1.32 0.19 25.96 85 <0.0001 0.248 0.142
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Figure 2.

Figure 2

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Forest plot for the association between PD-1 rs2227981 polymorphism and cancer susceptibility for CT vs. CC (A), TT vs. CC (B), CT+TT vs. CC (C), TT vs. CT+TT (D), and T vs. C (E).

In regard to PD-1 rs11568821 polymorphism, the findings indicated that this variant significantly decreased the overall cancer risk in heterozygous (OR = 0.79, 95% CI = 0.67–0.94, p = 0.006, AG vs. GG) and dominant (OR = 0.82, 95% CI = 0.70–0.96, p = 0.020, AG+AA vs. GG) genetic models (Table 3).

The pooled analysis proposed that PD-1 rs7421861 polymorphism significantly increased the risk of overall cancer in heterozygous (OR = 1.16, 95% CI = 1.02–1.33, p = 0.03, CT vs. TT) genetic models (Table 3).

No significant association was found between PD-1 rs2227982, rs36084323, and rs10204525 polymorphisms and cancer susceptibility (Table 3).

We performed stratified analyses and the findings are summarized in Table 4. We observed that PD-1 rs2227981 significantly decreased the risk of gastrointestinal (GI) cancer (OR = 0.68, 95% CI = 0.56–0.84, p = 0.000, TT vs. CC; OR = 0.60, 95% CI = 0.40–0.89, p = 0.011, TT vs. CT+CC; OR = 0.83, 95% CI = 0.75–0.91, p = 0.000, T vs. C), lung cancer (OR = 0.65, 95% CI = 0.44–0.97, p = 0.030, TT vs. CC; OR = 0.84, 95% CI = 0.71–0.99, p = 0.043, CT+TT vs. CC; OR = 0.83, 95% CI = 0.72–0.95, p = 0.009, T vs. C), and breast cancer (OR = 0.82, 95% CI = 0.70–0.06, p = 0.012, T vs. C).

Table 4.

Stratified analysis of PD-1 and PD-L1 polymorphisms with cancer susceptibility.

Variable No. CT vs. CC TT vs. CC CT+TT vs. CC TT vs. CT+CC T vs. C
PD-1 rs2227981 OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p
Asian 14 1.16 (0.94–1.43) 0.173 0.89 (0.71–1.12) 0.312 1.09 (0.90–1.32) 0.393 0.83 (0.66–1.04) 0.106 1.00 (0.87–1.14) 0.953
Population-based 13 1.12 (0.91–1.39) 0.276 0.88 (0.70–1.07) 0.175 1.06 (0.87–1.28) 0.571 0.81 (0.66–1.01) 0.060 0.97 (0.85–1.10) 0.611
Hospital-based 3 1.06 (0.72–1.61) 0.714 0.91 (0.53–1.59) 0.749 1.04 (0.68–1.57) 0.873 0.85 (0.57–1.26) 0.421 1.03 (0.76–1.41) 0.839
Gastrointestinal cancer 3 1.13 (0.73–1.76) 0.588 0.68 (0.56–0.84) 0.000 0.95 (0.71–1.27) 0.713 0.60 (0.40–0.89) 0.011 0.83 (0.75–0.91) 0.000
Lung cancer 3 0.91 (0.76–1.10) 0.324 0.65 (0.44–0.97) 0.030 0.84 (0.71–0.99) 0.043 0.69 (0.45–1.04) 0.079 0.83 (0.72–0.95) 0.009
Breast cancer 2 0.78 (0.56–1.08) 0.136 0.76 (0.53–1.10) 0.147 0.80 (0.59–1.01) 0.058 0.83 (0.59–1.17) 0.291 0.82 (0.70–0.96) 0.012
PD-1 rs2227982 CT vs. CC TT vs. CC CT+TT vs. CC TT vs. CT+CC T vs. C
Asian 10 1.02 (0.85–1.21) 0.845 1.04 (0.87–1.26) 0.655 1.02 (0.86–1.22) 0.790 1.00 (0.90–1.10) 0.921 1.02 (0.92–1.12) 0.708
Population-based 8 0.91 (0.73–1.12) 0.363 0.99 (0.73–1.33) 0.934 0.93 (0.741.16) 0.507 0.99 (0.83–1.17) 0.734 0.98 (0.85–1.14) 0.818
Hospital-based 3 1.22 (1.06–1.40) 0.006 1.16 (0.99–1.37) 0.067 1.20 (1.05–1.37) 0.008 1.02 (0.89–1.16) 0.806 1.08 (0.99–1.17) 0.077
Gastrointestinal cancer 4 1.18 (1.04–1.34) 0.011 1.12 (0.97–1.29) 0.133 1.16 (1.03–1.30) 0.017 1.00 (0.89–1.12) 0.989 1.06 (0.98–1.34) 0.146
Breast cancer 2 0.73 (0.59–0.90) 0.004 0.73 (0.57–0.93) 0.010 0.73 (0.60–0.89) 0.002 0.89 (0.74–1.09) 0.257 0.85 (0.76–0.96) 0.010
PD-1 rs7421861 CT vs. TT CC vs. TT CT+CC vs. TT CC vs. CT+TT C vs. T
Hospital-based 5 1.89 (1.01–1.40) 0.042 1.05 (0.79–1.39) 0.745 1.16 (0.98–1.38) 0.096 0.99 (0.74–1.31) 0.916 1.11 (0.95–1.29) 0.192
Population-based 2 1.09 (0.86–1.39) 0.478 0.89 (0.56–1.43) 0.630 1.07 (0.84–1.37) 0.565 0.88 (0.55–1.40) 0.586 1.04 (0.85–1.28) 0.692
Gastrointestinal cancer 5 1.19 (1.01–1.40) 0.042 1.05 (0.79–1.39) 0.745 1.16 (0.97–1.38) 0.096 1.00 (0.75–1.32) 0.979 1.11 (0.95–1.29) 0.192
Breast cancer 2 1.09 (0.86–1.39) 0.478 0.89 (0.56–1.43) 0.630 1.07 (0.84–1.37) 0.565 0.88 (0.55–1.40) 0.586 1.04 (0.85 (1.28) 0.692
PD-1 rs11568821 AG vs. GG AA vs. GG AG+AA vs. GG AA vs. AG+GG A vs. G
Population-based 7 0.80 (0.66–0.97) 0.020 1.02 (0.43–2.42) 0.968 0.86 (0.65–1.14) 0.288 1.09 (0.50–2.38) 0.833 0.92 (0.78–1.08) 0.294
Hospital-based 2 0.77 (0.55–1.10) 0.150 0.76 (0.20–2.90) 0.688 0.77 (0.55–1.09) 0.140 0.76 (0.21–3.02) 0.736 0.80 (0.58–1.09) 0.152
PD-1 rs36084323 AG vs. GG AA vs. GG AG+AA vs. GG AA vs. AG+GG A vs. G
Asian 6 0.95 (0.71–1.25) 0.691 1.05 (0.75–1.47) 0.769 0.86 (0.61–1.23) 0.412 1.05 (0.82–1.33) 0.715 0.86 (0.67–1.12) 0.259
Population-based 5 0.78 (0.50–1.21) 0.268 0.88 (0.47–1.63) 0.674 0.71 (0.42–1.22) 0.219 0.94 (0.61–1.45) 0.767 0.74 (0.49–1.12) 0.152
Hospital–based 2 1.13 (0.97–1.32) 0.127 1.26 (1.00–1.59) 0.052 1.17 (1.01–1.35) 0.042 1.93 (0.87–1.64) 0.277 1.12 (1.00–1.26) 0.05
PD-1 rs10204525 AG vs. AA GG vs. AA AG+GG vs. AA GG vs. AG+AA G vs. A
Gastrointestinal cancer 5 0.90 (0.76–1.07) 0.227 0.63 (0.45–1.04) 0.078 0.86 (0.70–1.04) 0.121 0.72 (0.48–1.06) 0.096 0.85 (0.71–1.02) 0.077
Population-based 3 0.85 (0.58–1.23) 0.382 0.60 (0.28–1.32) 0.203 0.80 (0.52–1.32) 0.312 0.65 (0.35–1.23) 0.186 0.80 (0.55–1.17) 0.246
Hospital-based 3 0.99 (0.88–1.22) 0.908 0.90 (0.63–1.29) 0.568 0.99 (0.88–1.11) 0.831 0.89 (0.60–1.32) 0.560 0.99 (0.90–1.08) 0.767
PD-L1 rs4143815 CG vs. GG CC vs. GG CG+CC vs. GG CC vs. CG+GG C vs. G
Gastrointestinal cancer 6 0.68 (0.48–0.97) 0.032 0.59 (0.37–0.96) 0.033 0.64 (0.43–0.95) 0.028 0.77 (0.58–1.02) 0.064 0.76 (0.59–0.98) 0.034
Hospital-based 6 0.71 (0.48–1.05) 0.087 0.60 (0.36–1.00) 0.051 0.67 (0.44–1.02) 0.059 0.75 (0.58–0.97) 0.030 0.76 (0.58–0.99) 0.043
Population-based 2 0.89 (0.68–1.18) 0.414 0.68 (0.29–1.59) 0.378 0.82 (0.55–1.23) 0.332 0.76 (0.36–1.59) 0.460 0.83 (0.53–1.30) 0.413
PD-L1 rs2890658 AC vs. AA CC vs. AA AC+CC vs. AA CC vs. AC+AA C vs. A
Lung cancer 3 1.74 (1.37–2.19) 0.000 2.48 (0.92–6.69) 0.072 1.77 (1.41–2.23) 0.000 2.29 (0.85–6.16) 0.101 1.72 (1.39–2.13) 0.000
Gastrointestinal cancer 2 4.34 (0.13–148.07) 0.415 4.43 (0.17–112.70) 0.368 0.76 (0.53–1.10) 0.141 0.84 (0.66–1.08) 0.179 0.84 (0.69–1.01) 0.070
Hospital-based 3 1.42 (0.72–2.96) 0.317 1.61 (0.52–4.98) 0.409 1.45 (0.72–2.92) 0.296 1.45 (0.57–3.73) 0.439 1.46 (0.75–2.82) 0.266
Population-based 2 6.30 (0.39–103.18) 0.197 6.85 (0.60–78.36) 0.122 1.23 (0.67–2.26) 0.503 0.90 (0.56–1.37) 0.636 1.13 (0.65–1.97) 0.661
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Furthermore, we found that the PD-1 rs2227982 was associated with an increased risk of cancer in hospital based studies (OR = 1.22, 95% CI = 1.06–1.40, p = 0.006, CT vs. CC; OR = 1.20, 95% CI = 1.05–1.37, p = 0.008, CT+TT vs. CC). We also found a negative correlation between the PD-1 rs2227982 polymorphism and the risk of gastrointestinal cancer (OR = 1.18, 95% CI = 1.04–1.34, p = 0.011, CT vs. CC; OR = 1.16 (95% CI = 1.03–1.30, p = 0.017, CT+TT vs. CC) and breast cancer risk (OR = 0.73, 95% CI = 0.59–0.90, p = 0.004, CT vs. CC; OR = 0.73, 95% CI = 0.57–0.93, p = 0.010, TT vs. CC; OR = 73, 95% CI = 0.60–0.89, p = 0.002, CT+TT vs. CC; OR = 0.85, 95% CI = 76–0.96, p = 0.010, T vs. C). With reference to the PD-1 rs7421861, our finding proposed that this variant significantly increased the risk of cancer in hospital based studies (OR = 1.89, 95% CI = 1.01–1.40, p = 0.042, CT vs. TT) as well as gastrointestinal cancer (OR = 1.19, 95% CI = 1.01–1.40, p = 0.042, CT vs. CC). Moreover, a significantly reduce cancer risk in population-based studies (OR = 0.80, 95% CI = 0.66–0.97, p = 0.020, AG vs. GG) was observed regarding PD-1 rs11568821 variant. The PD-1 rs36084323 variant was however associated with an increased risk of cancer in hospital-based studies (OR = 1.17, 95% CI = 1.01–1.35, p = 0.042, AG+AA vs. GG).

2.2.2. PD-L1 Polymorphisms and Cancer Risk

The pooled ORs results for the relationship between the PD-L1 rs4143815 and rs2890658 polymorphisms and the risk of cancer are shown in Table 3. The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41–0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50–0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60–0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63–0.96, p = 0.02) genetic models (Table 3 and Figure 3). The pooled analysis did not support an association between PD-L1 rs2890658 polymorphism and risk of cancer susceptibility (Table 3).

Figure 3.

Figure 3

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Forest plot of the relationship between PD-L1 rs4143815 polymorphism and cancer susceptibility for CG vs. GG (A), CC vs. GG (B), CG+CC vs. GG (C), CC vs. CG+GG (D), and C vs. G (E).

We did stratified analysis (Table 4) and the findings revealed that PD-L1 rs4143815 polymorphism significantly reduced the risk of gastrointestinal cancer (OR = 0.68, 95% CI = 0.48–0.97, p = 0.032, CC vs. GG; OR = 0.59, 95% CI = 0.37–0.96, p = 0.033, CC vs. GG; OR = 0.64, 95% CI = 0.43–0.95, p = 0.028, CG+CC vs. GG; OR = 0.76, 95% CI = 0.59–0.98, p = 0.034, C vs. G) and hospital-based studies (OR = 0.75, 95% CI = 0.58–0.97, p = 0.030, CC vs. CG+GG; OR = 0.76, 95% CI = 0.58–0.99, p = 0.043, C vs. G). In regard to PD-L1 rs2890658, a positive correlation between this variant and the risk of lung cancer (OR = 1.74, 95% CI = 1.37–2.19, p = 0.000, AC vs. AA; OR = 1.77, 95% CI = 1.41–2.23, p = 0.000, AC+CC vs. AA; OR = 1.72, 95% CI = 1.39–2.13, p = 0.000 C vs. A) was observed (Table 4).

2.3. Heterogeneity

As shown in Table 3, heterogeneity between the studies regarding the PD-1 rs2227981, PD-1 rs36084323, PD-1 rs10204525, and PD-L1 rs4143815 was observed in all genetic models. For PD-1 rs2227982 polymorphism, our results showed no evidence of heterogeneity in the recessive model (TT vs. CT+CC). Regarding PD-1 rs11568821, heterogeneity was not observed in the heterozygous, homozygous, dominant, and recessive genetic models. Similarly, no evidence of heterogeneity in the heterozygous, homozygous, and recessive genetic models of PD-1 rs7421861 was found. Heterogeneity was not detected in the homozygous and recessive genetic models of the PD-L1 rs2890658.

2.4. Publication Bias

The potential publication bias of the studies included in the present meta-analysis was examined by Begg’s funnel plot and Egger’s test. The results of publication bias are summarized in Table 3. Based on the above analysis, no publication bias for the association of PD-1 rs2227982, PD-1 rs7421861, and PD-L1 rs4143815 variants in all genetic models and cancer risk was demonstrated (Table 3 and Figure 4).

Figure 4.

Figure 4

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The funnel plot of PD-L1 rs4143815 for the test of publication bias for CG vs. GG (A), CC vs. GG (B), CG+CC vs. GG (C), CC vs. CG+GG (D), and C vs. G (E).

As presented in Table 3 and Figure 5, no publication bias was observed in recessive genetic model of PD-1 rs2227981. Obvious publication bias was not found in the heterozygous, dominant, and allele genetic models of the PD-1 rs11568821 and PD-L1 rs2890658 (Table 3). Moreover, the publication bias was not observed in heterozygous, dominant, recessive, and allele genetic models of the PD-1 rs36084323 and PD-1 rs10204525. (Table 3).

Figure 5.

Figure 5

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The funnel plot of PD-1 rs2227981 polymorphism for the test of publication bias for CT vs. CC (A), TT vs. CC (B), CT+TT vs. CC (C), TT vs. CT+TT (D), and T vs. C (E).

2.5. Sensitivity Analysis

Sensitivity analysis was conducted by replicating analysis after neglecting one study at a time to estimate the effect of quality of studies on the final findings. Taken together, our findings from the meta-analysis of the correlation between analyzed polymorphisms and cancer susceptibility remained unchanged in the heterozygous (PD-1 rs2227982, PD-1 rs36084323 and PD-1 rs10204525), homozygous (PD-1 rs2227982, PD-1 rs7421861, PD-1 rs36084323, PD-1 rs10204525 and PD-L1 rs2890658), dominant (PD-1 rs36084323 and PD-1 rs10204525), recessive (PD-1 rs2227982, PD-1 rs7421861, PD-1 rs36084323 and PD-L1 rs2890658), and allele (PD-1 rs2227982, PD-1 rs7421861 PD-1 rs10204525 and PD-L1 rs2890658) genetic models (Figure 6). In regard to PD-L1 rs4143815, the findings changed in the heterozygous, homozygous, dominant, recessive, and allele genetics models (Figure 7).

Figure 6.

Figure 6

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Sensitivity analyses for studies on PD-1 rs2227981 polymorphism and cancer susceptibility for CG vs. GG (A), CC vs. GG (B), CG+CC vs. GG (C), CC vs. CG+GG (D), and C vs. G (E).

Figure 7.

Figure 7

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Sensitivity analyses for studies on PD-L1 rs4143815 polymorphism and cancer susceptibility for CG vs. GG (A), CC vs. GG (B), CG+CC vs. GG (C), CC vs. CG+GG (D), and C vs. G (E).

3. Discussion

It has been proposed that environmental and genetic factors contribute to cancer development [53,54]. Single nucleotide polymorphisms (SNPs) can be considered as biological markers that help scientists to recognize genes that are related to cancer [55].

PD-1 and PD-L1 are involved in the regulation of programmed cell death, which is the regulator of cancer cell proliferation as well as primary response in many cancer therapy strategies. Several studies have investigated the association between PD-1 as well as PD-L1 polymorphisms and the risk of various types of cancers; however, the findings remain discrepant. This meta-analysis provides, for the first time a quantitative estimated of the association between six SNPs of PD-1 and two SNPs of PD-L1 gene and cancer susceptibility. The findings indicated that PD-1 rs2227981 and rs11568821 polymorphisms as well as PDL-1 rs4143815 variant significantly decreased the overall cancer risk, while PD-1 rs7421861 polymorphism significantly increased the risk of overall cancer. Our findings revealed no significant association between PD-1 rs2227982, PD-1 rs36084323, PD-1 rs10204525, and PD-L1 rs2890658 polymorphisms and overall cancer risk.

We performed stratified analyses and our findings indicate that PD-1 rs2227981 significantly decreased the risk of gastrointestinal cancer, lung cancer and breast cancer. The PD-1 rs2227982 was associated with increased risk of cancer in hospital-based studies and lower risk of gastrointestinal and breast cancer. Similarly to PD-1 rs7421861, the PD-1 rs7421861 and PD-1 rs36084323 variants significantly increased the risk of cancer in hospital-based studies. The PD-1 rs11568821 was linked to reduce risk of cancer in population-based studies. Moreover, our findings revealed that PD-L1 rs4143815 polymorphism significantly reduced the risk of gastrointestinal cancer and hospital-based studies. A positive correlation between PD-L1 rs2890658 variant and the risk of lung cancer was observed.

Recently, Zou et al. [56] performed a meta-analysis of the association between PD-L1 rs4143815 polymorphism and the risk of cancer and found also a significant association between this variant and cancer risk, which is in line with our findings. Like our results, a meta-analysis conducted by Da et al. [57] revealed no significant association between PD-1 rs36084323 polymorphism and overall cancer susceptibility. Similar to previous meta-analysis conducted by Zhang et al. [58], we have also found that PD-1 rs2227981 and rs11568821 polymorphisms were associated with decreased cancer susceptibility. In another study, Dong et al. [59] conducted a meta-analysis aimed to inspect the associations between PD-1 rs2227981, rs2227982, rs7421861, and rs11568821 polymorphisms and cancer risk. There were seven studies involving 3395 cases and 2912 controls for PD-1 rs2227981, four studies including 1961 cases and 2390 controls for PD-1 rs2227982, four studies with 1975 cases and 2403 controls for PD-1 rs7421861, and four studies for PD-1 rs11568821 variant and cancer risk. They have found that rs2227981 and rs11568821 polymorphisms significantly decreased the risk of cancer. Mamat et al. [60] conducted a meta-analysis of six studies involving 1427 cases and 1811 controls and have observed no significant association between PD-1 rs2227981 polymorphism and the risk of cancer.

Nevertheless, the number of cases and controls as well as the number of polymorphisms in our meta-analysis is higher than in those previously published meta-analysis studies.

It has been proposed that gene expression could be potentially affected by genetic polymorphisms [21,61,62,63]. Alterations in the expression of PD-1 and PDL-1 were detected in many cancer types including gastric cancer, lung cancer, thyroid cancer, laryngeal carcinoma, extrapulmonary small cell carcinoma, and breast cancer [63,64,65,66,67,68,69].

PD-1/PD-L1 axis impairs T cell activation by preventing Ras-Raf-MEK-ERK and PI3K-AKT signaling pathways, which are mainly believed to promote proliferation and differentiation of T cell [70]. The inhibitory regulation of PD-1/PD-L1 is typically compared to a brake in T cell activation [71]. PD-L1 is exerted by tumors to escape from immune system. Tumor-specific PD-L1-expression was not prognostic in colorectal cancer, while high immune cell-specific PD-1 expression was associated with a prolonged overall survival [72]. It has been revealed that high expression of PD-1 on peripheral blood T cell subsets is correlated with poor prognosis of metastatic gastric cancer [73]. Fang et al. [74] reported that the peripheral blood PD-1 expression was significantly higher in breast cancer patients than benign breast tumors. PD-1 and PD-L1 expression have been shown to be associated with adverse clinicopathological features in clear cell renal carcinoma [75].

This meta-analysis has however several limitations. Firstly, there are relatively small sample sizes of studies for some polymorphisms that should be expanded. Secondly, we have included in this meta-analysis only studies published in English, thus publication bias may have occurred. Thirdly, obvious heterogeneities were found in certain polymorphisms. Differences in ethnic background, type of cancer, and other baseline characteristics of participants may contribute to between-study heterogeneities. Lastly, gene-gene and gene-environment interactions which may affect cancer susceptibility were not evaluated in this meta-analysis due to lack of sufficient data. Therefore, the results of this meta-analysis should be cautiously interpreted.

In conclusion, the current meta-analysis suggests that rs2227981 and rs11568821 polymorphisms of PD-1 and the rs4143815 polymorphism of PD-L1 were associated with protection against cancer, while PD-1 rs7421861 polymorphism significantly increased cancer risk.

4. Methods

4.1. Literature Search

We searched PubMed, Web of Science, Scopus, and Google Scholar databases for publications that studied the association between PD-1 and PD-L1 polymorphisms and cancer risk. The last search was updated on 18 December 2019. The following search terms were used; “programmed cell death 1 or PDCD1 or PD-1, or CD279, or programmed death-1-ligand 1 or CD274 or B7-H1” and “polymorphism or single nucleotide polymorphism or SNP or variation” and “cancer or carcinoma, or tumor”.

The process of recognizing eligible studies is presented in Figure 1. The inclusion and exclusion criteria were as follows. (1) The studies evaluated the association between the PD-1 and PD-L1 polymorphisms and cancer risk, (2) studies with necessary information on genotype or allele frequencies to estimate ORs and 95% Cis, (3) studies with human subjects, and (4) case-control design. We excluded reviews, conference papers, and other studies that were published as abstracts only.

4.2. Data Extraction

The data were recovered from eligible articles independently by two authors. Disagreements were discussed with the third investigator. The following information was recorded for each study: first author’s name, publication year, patient’s nationality, genotypes, and allele frequencies.

4.3. Statistical Analysis

We performed a meta-analysis to assess the association between PD-1 and PD-L1 polymorphisms and cancer susceptibility. The observed genotype frequencies in the controls were tested for Hardy-Weinberg equilibrium (HWE) using the chi-squared test.

Odds ratio (OR) and 95% confidence interval (CI) were calculated to evaluate the association between PD-1 and PD-L1 polymorphisms and cancer risk in five genetic models, which were heterozygous, homozygous, dominant, recessive, and allele. The strength of the association between each polymorphism and cancer risk was assessed by pooled odds ratios (ORs) and their 95% confidence intervals (CIs). The Z-test was used for statistical significance of the pooled OR. We estimated the between-study heterogeneity by the Q-test and I2 test: If I2 < 50% and P > 0.1, the fixed effects model was used to estimate the ORs and the 95% CI; otherwise, the random effects model was applied.

We evaluated publication bias using funnel plots for visual inspection and conducting quantitative estimations with Egger’s test.

Sensitivity analysis was achieved by excluding each study in turn to assess the stability of the results. All analyses were achieved by STATA 14.1 software (Stata Corporation, College Station, TX, USA).

5. Conclusions

The findings of our meta-analysis proposed that PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms associated with overall cancer susceptibility. Further well-designed studies with large sample sizes are warranted to confirm our findings.

Acknowledgments

Andrzej Malecki was supported by Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education in Katowice. Saeid Ghavami was supported by Research Manitoba New Investigators Operating Grant and CancerCare Manitoba Operating grant.

Author Contributions

M.H. conceptualized and designed the study, conducted statistical analysis, and proofread the final draft. S.S., S.K., and A.M.-R. searched the literature, extracted the data, and prepared the figures. S.G. and E.W. conducted the final proofread, discussed the results, and prepared the final draft of manuscript. A.M. conducted the final proofread and provided information about cancer involvement. All authors reviewed the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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