Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese

Haoming Mai; Jiaxuan Chen; Haitao Chen; Zhiwei Liu; Guanlin Huang; Jialin Wang; Qianyi Xiao; Weihua Ren; Bin Zhou; Jinlin Hou; Deke Jiang

doi:10.2147/JHC.S321919

Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese

J Hepatocell Carcinoma. 2021 Aug 16:8:951-961. doi: 10.2147/JHC.S321919. eCollection 2021.

Authors

Haoming Mai^#¹, Jiaxuan Chen^#¹, Haitao Chen^#^{1

2}, Zhiwei Liu^#³, Guanlin Huang¹, Jialin Wang¹, Qianyi Xiao⁴, Weihua Ren⁵, Bin Zhou¹, Jinlin Hou¹, Deke Jiang¹

Affiliations

¹ State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
² School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, People's Republic of China.
³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁴ School of Public Health, Fudan University, Shanghai, 200032, People's Republic of China.
⁵ Central Laboratory, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan Province, 471009, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive.

Methods: With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) <0.20). A total of 14,930 variants within the MHC region were genotyped or imputed.

Results: We identified two variants, rs114401688 (P = 1.05 × 10^-6, P_FDR = 2.43 × 10^-3) and rs115126566 (P = 9.04 × 10^-5, P_FDR = 1.77 × 10^-1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1*04 and HLA-DRB1*04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥50, P = 0.03).

Discussion: Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.

Keywords: HBV; MHC; fine mapping; hepatocellular carcinoma; susceptibility.

Grants and funding

This study was supported by the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01S131), the National Science and Technology Major Project (No. 2017ZX10202202 and 2018ZX10301202), the General Programs from the National Natural Science Foundation of China (No. 81472618, 81670535 and 81802828), the National Natural Science Foundation of China, China (No. 82060458 and 81802833) the General Program from the Natural Science Foundation of Guangdong Province (No. 2019A1515011423), the Key-Area Research and Development Program of Guangdong Province (No. 2019B020227004), the Innovative Research Team Project of Guangxi Province (No. 2017GXNSFGA198002), the Dean Fund of Nanfang Hospital, Southern Medical University (No. 2018Z005), the Grant for Recruited Talents to Start Scientific Research from Nanfang Hospital, and the Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (No. 2017J001), Natural Science Foundation of Tibet Autonomous Region (ZRKX2018000153).