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; Yong-Lin Cai; Yuming Zheng; Zhe Zhang; Guangwu Huang; Ingemar Ernberg; Minzhong Tang; Weimin Ye; Hans-Olov Adami; Yi-Xin Zeng; Xihong Lin

doi:10.1016/j.xgen.2023.100474

Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation

Cell Genom. 2024 Feb 14;4(2):100474. doi: 10.1016/j.xgen.2023.100474. Epub 2024 Jan 9.

Authors

Miao Xu¹, Ruimei Feng², Zhonghua Liu³, Xiang Zhou⁴, Yanhong Chen⁵, Yulu Cao⁵, Linda Valeri⁶, Zilin Li⁷, Zhiwei Liu⁸, Su-Mei Cao⁵, Qing Liu⁵, Shang-Hang Xie⁵, Ellen T Chang⁹, Wei-Hua Jia⁵, Jincheng Shen¹⁰, Youyuan Yao¹¹, Yong-Lin Cai¹², Yuming Zheng¹², Zhe Zhang¹³, Guangwu Huang¹³, Ingemar Ernberg¹⁴, Minzhong Tang¹³, Weimin Ye¹⁵, Hans-Olov Adami¹⁶, Yi-Xin Zeng¹⁷, Xihong Lin¹⁸

Affiliations

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
² Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030012, Shanxi, China.
³ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁴ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong, China.
⁵ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁶ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁷ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; School of Mathematics and Statistics, Northeast Normal University, Changchun, China.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
⁹ Center for Health Sciences, Menlo Park, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
¹¹ Department of Geriatric Oncology, Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
¹² Guangxi Health Commission Key Laboratory of Molecular Epidemiology of Nasopharyngeal Carcinoma, Wuzhou Red Cross Hospital, Wuzhou, China.
¹³ Department of Otolaryngology/Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
¹⁴ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Health Statistics & Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China. Electronic address: ywm@fjmu.edu.cn.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Clinical Effectiveness Group, Institute of Health and Society, University of Oslo, Oslo, Norway. Electronic address: hadami@hsph.harvard.edu.
¹⁷ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: zengyx@sysucc.org.cn.
¹⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. Electronic address: xlin@hsph.harvard.edu.

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.

Keywords: Epstein-Barr virus; HLA polymorphism; causal inference; genetic susceptibility to cancer; interaction; mediation; nasopharyngeal carcinoma.

MeSH terms

Case-Control Studies
Epstein-Barr Virus Infections* / genetics
Herpesvirus 4, Human / genetics
Humans
Nasopharyngeal Carcinoma / genetics
Nasopharyngeal Neoplasms* / epidemiology
Polymorphism, Single Nucleotide / genetics

Abstract

MeSH terms

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