Functional genetic variants in immune-checkpoint molecules and susceptibility to Nasopharyngeal carcinoma in a Tunisian case-control study.

BACKGROUND: Immune checkpoint pathways regulating T cell activity are key targets in cancer therapy. Genetic variations in checkpoint molecules (CTLA-4, PD-1, PD-L1) can alter signaling pathways, affecting cancer risk and treatment response in various types of malignancies.

METHODS: This study aimed to investigate associations between common polymorphisms in immune-regulating genes (CTLA-4, PDCD1 and CD274) and susceptibility to nasopharyngeal carcinoma (NPC) in the Tunisian population. We analyzed six polymorphisms: rs231775 and rs3087243 (CTLA-4), rs2227981, rs2227982, and rs36084323 (PDCD1), and rs2890658 (CD274) in a case-control study which enrolled 61 Tunisian NPC patients and 150 matched healthy controls using the PCR-RFLP method.

RESULTS: For the rs231775 SNP, our findings showed a significant association between the AA genotype and increased NPC susceptibility in the recessive model (GG + AG vs. AA) (pc=0.006, OR = 2.5, 95% CI: [1.35-4.6]). Further, the haplotype analysis showed that the rs231775 > A-rs3087243 > A-rs36084323 > G-rs2227982 > C-rs2227981 > C risk haplotype was significantly more expressed in NPC patients (p = 0.044, OR = 1.64, 95% CI: [1.02-2.63]). The phenotype-genotype association revealed that the rs231775 > AA genotype was significantly associated with clinical manifestations. We also confirmed that the rs2890658 > CC genotype was significantly associated with increased risk of NPC under the recessive model (AA + CA vs. CC), p = 0.0001, OR = 3.2, 95% CI: [1.71 - 5.96]. In addition, the rs2890658 > C variant had a 2.4-fold higher risk of NPC in comparison with the A allele (p = 0.0009, OR = 2.4, 95% CI: [1.42 - 4.08]).

CONCLUSION: Our results suggest that the CTLA-4_rs231775 > AA and CD274_rs2890658 > CC genotypes could be considered as predisposition factors for NPC. These findings could pave the way for future investigations into NPC pathogenesis and assessing CTLA-4, PDCD1, and CD274 as personalized therapeutic targets.