Retrospective Cohort Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2021; 27(37): 6262-6276
Published online Oct 7, 2021. doi: 10.3748/wjg.v27.i37.6262
Hepatitis B virus persistent infection-related single nucleotide polymorphisms in HLA regions are associated with viral load in hepatoma families
Ai-Ru Hsieh, Cathy S J Fann, Hung-Chun Lin, Jennifer Tai, Sen-Yung Hsieh, Dar-In Tai
Ai-Ru Hsieh, Department of Statistics, Tamkang University, New Taipei City 25137, Taiwan
Cathy S J Fann, Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 11529, Taiwan
Hung-Chun Lin, Jennifer Tai, Sen-Yung Hsieh, Dar-In Tai, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan
Author contributions: Tai DI is the guarantor and designed the study; Hsieh AR and Fann CSJ participated in the statistical analysis and data interpretation; Lin HC, Tai J, Hsieh SY and Tai DI participated in the data acquisition; Fann CSJ revised the manuscript critically for important intellectual content.
Supported by Chang Gung Memorial Hospital, No. CMRPG3C0701; and National Science Council, No. NSC101-2314-B-182A-025-MY3 and No. MOST 107-2314-B-039-059.
Institutional review board statement: The study was approved by the institutional review board of Chang Gung Memorial Hospital, Taiwan (IRB 104-2596).
Informed consent statement: Written informed consent was obtained from all participants before the study. All experiments and data comparisons were carried out in compliance with relevant laws and guidelines, and in accord with the ethical standards of the Declaration of Helsinki.
Conflict-of-interest statement: The authors declare that they have no conflicting interests.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dar-In Tai, MD, PhD, Professor, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5 Fuxing Street, Guishan District, Taoyuan 33305, Taiwan. tai48978@cgmh.org.tw
Received: April 8, 2021
Peer-review started: April 8, 2021
First decision: June 26, 2021
Revised: July 6, 2021
Accepted: September 1, 2021
Article in press: September 1, 2021
Published online: October 7, 2021
Abstract
BACKGROUND

Genome-wide association studies from Asia indicate that HLA-DP and HLA-DQ loci are important in persistent hepatitis B virus (HBV) infections. One of the key elements for HBV-related carcinogenesis is persistent viral replication and inflammation.

AIM

To examine genetic and nongenetic factors with persistent HBV infection and viral load in families with hepatocellular carcinoma (HCC).

METHODS

The HCC families included 301 hepatitis B surface antigen (HBsAg) carriers and 424 noncarriers born before the nationwide vaccination program was initiated in 1984. Five HBV-related single nucleotide polymorphisms (SNPs) — rs477515, rs9272105, rs9276370, rs7756516, and rs9277535 — were genotyped. Factors associated with persistent HBV infection and viral load were analyzed by a generalized estimating equation.

RESULTS

In the first-stage persistent HBV study, all SNPs except rs9272105 were associated with persistent infection. A significantly higher area under the reciprocal operating characteristic curve for nongenetic factors vs genetic factors (P < 0.001) suggests that the former play a major role in persistent HBV infection. In the second-stage viral load study, we added 8 HBsAg carriers born after 1984. The 309 HBsAg carriers were divided into low (n = 162) and high viral load (n = 147) groups with an HBV DNA cutoff of 105 cps/mL. Sex, relationship to the index case, rs477515, rs9272105, and rs7756516 were associated with viral load. Based on the receiver operating characteristic curve analysis, genetic and nongenetic factors affected viral load equally in the HCC family cohort (P = 0.3117).

CONCLUSION

In these east Asian adults, the mechanism of persistent HBV infection-related SNPs was a prolonged viral replication phase.

Keywords: Generalized estimating equation, Genetic polymorphism, Genome-wide association study, Hepatitis B surface antigen, Hepatitis B virus, Replication

Core Tip: Hepatitis B virus (HBV)-related single nucleotide polymorphisms (SNPs) have been identified in East Asians. We evaluated five SNPs and nongenetic factors associated with HBV infection in a hepatocellular carcinoma family cohort. The factors were correlated with hepatitis B surface antigen (HBsAg) in the first-stage and with HBV viral load in the second-stage. The SNPs, sex, generation, and index case HBsAg contributed to persistent HBV infection. Neonatal tolerance and SNPs in the HLA loci were both independently associated with persistent HBV infection. A prolonged HBV replication phase in parents could be the main mechanism of persistent HBV infection in children in East Asia.