Impact of the cytotoxic T-lymphocyte associated antigen-4 rs231775 A/G polymorphism on cancer risk

Haiyan Pan; Zebin Shi; Lei Gao; Li Zhang; Shuzhang Wei; Yin Chen; Chao Lu; Jianzhong Wang; Li Zuo; Lifeng Zhang

doi:10.1016/j.heliyon.2023.e23164

Impact of the cytotoxic T-lymphocyte associated antigen-4 rs231775 A/G polymorphism on cancer risk

Heliyon. 2023 Dec 3;9(12):e23164. doi: 10.1016/j.heliyon.2023.e23164. eCollection 2023 Dec.

Authors

Haiyan Pan¹, Zebin Shi², Lei Gao², Li Zhang², Shuzhang Wei², Yin Chen², Chao Lu², Jianzhong Wang³, Li Zuo², Lifeng Zhang²

Affiliations

¹ Department of Urology, Affiliated Hospital of Jiangnan University, Hefeng Road 1000, Wuxi, 214000, PR China.
² Department of Urology, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, Jiangsu Province, PR China.
³ Department of Hospital Office, Affiliated Hospital of Jiangnan University, Hefeng Road 1000, Wuxi, 214000, PR China.

Abstract

Background: Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immunosuppressive checkpoint that is involved in the development and metastasis of cancers. Several studies revealed that CTLA-4 rs231775A/G polymorphism may be associated with the risk of cancer in some populations, but the conclusions of these studies are not consistent.

Methods: We conducted a pooled analysis with eligible studies to explore the association between the CTLA-4 rs231775 variant and cancer risk. Additionally, we used in silico tools to evaluated the expression of CTLA-4 on urinary system cancer. Moreover, we adopted the enzyme-linked immunosorbent assay (ELISA), and Gene Set Enrichment Analysis (GSEA) to investigate the effects of CTLA-4 on bladder cancer (BLCA).

Results: In total, 92 case-control studies involving 29,987 patients with cancer and 36,484 healthy individuals (controls) were included in the pooled analysis. In the stratified analysis based on cancer type, the rs231775 A/G polymorphism was associated with increased bladder cancer risk in the heterozygote contrast model (OR = 1.23, 95% CI = 1.01-1.51, P = 0.040). The race-stratified analysis revealed that East Asians with the GG genotype had a 12% lower risk of developing cancer than those with the GA + AA genotype (95% CI = 0.81-0.95, P = 0.001). The in silico analysis showed that CTLA-4 expression was augmented in patients with BLCA. The ELISA results revealed that CTLA-4 expression was reduced in patients with BLCA carrying the AA genotype. Several signaling pathways, including cytokine-cytokine receptor interactions and T-cell receptor signaling, were associated with CTLA-4 expression.

Conclusion: The CTLA-4 rs231775 A/G polymorphism is associated with cancer risk in East Asian population. This polymorphism is especially associated with BLCA.

Keywords: Analysis; CTLA-4; Cancer; Variant.