Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation
Miao Xu, Ruimei Feng, Zhonghua Liu, Xiang Zhou, Yanhong Chen, Yulu Cao, Linda Valeri, Zilin Li, Zhiwei Liu, Su‐Mei Cao, Qing Liu, Shang-Hang Xie, Ellen T. Chang, Wei‐Hua Jia, Jincheng Shen, Youyuan Yao, Yonglin Cai, Yuming Zheng, Zhe Zhang, Guangwu Huang, Ingemar Ernberg, Minzhong Tang, Weimin Ye, Hans‐Olov Adami, Yi‐Xin Zeng, Xihong Lin
Abstract
Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03-6.14; rs2894207, RERI = 3.37, 95% CI = 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.