Background:Epstein-Barr virus(EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma(NPC),which has a high incidence in certain regions.This study aimed to address how EBV variations contribute to the risk of NPC.Methods:Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1,a multistage association study was conducted to identify EBV variations associated with NPC risk.A protein degradation assay was performed to characterize the functional relevance of the RPMS1 variations.Results:Based on EBV-encoded RPMS1 variations,a single nucleotide polymorphism(SNP) in the EBV genome(locus 155391:G>A,named Gl 55391 A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China[P < 0.001,odds ratio(OR) = 4.47,95%confidence interval(CI) 2.71-7.37].The results were further validated in three independent cohorts from the NPC endemic region(P < 0.001,OR = 5.20,95%CI3.18-8.50 in 168 cases vs.241 controls,and P < 0.001,OR = 5.27,95%CI 4.06-6.85 in 726 cases vs.880 controls) and a non-endemic region(P < 0.001,OR = 7.52,95%CI 3.69-15.32 in 58 cases vs.612 controls).The combined analysis in 1109 cases and 2052 controls revealed that the SNP Gl 55391 A was strongly associated with NPC(P_(combined) < 0.001,OR = 5.27,95%CI 4.31-6.44).Moreover,the frequency of the SNP Gl 55391 A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies.Furthermore,the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein.Conclusions:Our study identified an EBV variation specifically and significantly associated with a high risk of NPC.These findings provide insights into the pathogenesis of NPC and strategies for prevention. Background: Epstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aims to address how EBV variations contribute to the risk of NPC. Methods : Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1, a multistage association study was conducted to identify EBV variations associated with NPC risk. A protein degradation assay was performed to characterize the functional relevance of RPMS1 variations. Results: Based on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G> A, named Gl 55391 A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P <0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71-7.37]. The results were even validated in three independent cohorts from the NPC endemic region (P <0.001, OR = % CI3.18-8.50 in 168 cases vs. 241 controls, and P <0.001 OR = 5.27, 95% CI 4.06-6.85 in 726 cases vs. .880 controls) and a non-endemic region (P <0.001, OR = 7.52, 95% CI 3.69 -15.32 in 58 cases vs. 612 controls). The combined analysis in 1109 cases and 2052 controls revealed that the SNP Gl 55391 A was strongly associated with NPC (P_ (combined) <0.001, OR = 5.27, 95% CI 4.31-6.44 ). Coreover, the frequency of the SNP Gl 55391 A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Fermentmore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein. Conclusions: Our study identified an EBV variation specifically and significantly associated with a high risk of NPC. The findings provide insights into the pathogenesis of NPC and strategies for prevention.