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

Abstract

Haoming Mai,1,* Jiaxuan Chen,1,* Haitao Chen,1,2,* Zhiwei Liu,3,* Guanlin Huang,1 Jialin Wang,1 Qianyi Xiao,4 Weihua Ren,5 Bin Zhou,1 Jinlin Hou,1 Deke Jiang1 1State 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; 2School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China; 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; 4School of Public Health, Fudan University, Shanghai, 200032, People’s Republic of China; 5Central Laboratory, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan Province, 471009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Deke Jiang; Jinlin HouState 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 ChinaTel [phone]; [phone]Email [email protected]; [email protected]: 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, PFDR = 2.43 × 10− 3) and rs115126566 (P = 9.04 × 10− 5, PFDR = 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: fine mapping, susceptibility, MHC, hepatocellular carcinoma, HBV

Keywords

• fine mapping
• susceptibility
• mhc
• hepatocellular carcinoma
• hbv