The interaction and mediation effects between the host genetic factors and Epstein–Barr virus VCA‐IgA in the risk of nasopharyngeal carcinoma

Abstract

AbstractPrevious studies have demonstrated strong associations between host genetic factors and Epstein–Barr virus (EBV) VCA‐IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA‐IgA on NPC risk is not well understood. In this two‐stage case–control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome‐wide association study‐derived polygenic risk score [PRS]) and EBV VCA‐IgA antibody level in the NPC risk. We employed a four‐way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA‐IgA. We consistently found a significant interaction between the PRS and EBV VCA‐IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85–3.10; replication population: SI = 3.10, 95% CI = 2.17–4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA‐IgA antibody. We also observed an obvious dose–response relationship between the PRS and EBV VCA‐IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic‐EBV interaction, while the risk effects mediated by EBV VCA‐IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA‐IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.