Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2017; 23(23): 4222-4232
Published online Jun 21, 2017. doi: 10.3748/wjg.v23.i23.4222
Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naïve Korean patients infected with genotype C2
Ji-Eun Kim, So-Young Lee, Hong Kim, Ki-Jeong Kim, Won-Hyeok Choe, Bum-Joon Kim
Ji-Eun Kim, So-Young Lee, Hong Kim, Bum-Joon Kim, Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea
Ki-Jeong Kim, Department of Microbiology, School of Medicine, Joong-Ang University, Seoul 110-799, South Korea
Won-Hyeok Choe, Department of Internal Medicine, Konkuk University School of Medicine, Seoul 110-799, South Korea
Author contributions: Kim BJ conceived this research and participated in its design and coordination; Kim JE, Lee SY and Kim H performed the experiments; Kim JE and Lee SY analyzed and interpreted the data; Kim BJ, Kim KJ and Choe WH contributed the reagents, materials, and analysis tools; Kim JE and Lee SY wrote and reviewed the manuscript; all authors approved the final manuscript; Kim JE and Lee SY are equally contributed to this work.
Supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology No. NRF-2015R1C1A1A02037267; and Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, South Korea, No. HI14C0955.
Institutional review board statement: All serum samples collected from patients at the Konkuk University Hospital and Seoul National University Hospital, South Korea. The ethical permission was obtained for participation in the study.
Conflict-of-interest statement: There was no conflict of interest exists.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Dr. Bum-Joon Kim, Professor, Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea. kbumjoon@snu.ac.kr
Telephone: +82-2-7408316 Fax: +82-2-7430881
Received: January 13, 2017
Peer-review started: January 14, 2017
First decision: March 16, 2017
Revised: March 28, 2017
Accepted: May 9, 2017
Article in press: May 9, 2017
Published online: June 21, 2017
Abstract
AIM

To report naturally occurring mutations in the reverse transcriptase region (RT) of hepatitis B virus (HBV) polymerase from treatment naïve Korean chronic patients infected with genotype C2.

METHODS

Here, full-length HBV reverse transcriptase RT sequences were amplified and sequenced from 131 treatment naïve Korean patients chronically infected with hepatitis B genotype C2. The patients had two distinct clinical statuses: 59 patients with chronic hepatitis (CH) and 72 patients with hepatocellular carcinoma (HCC). The deduced amino acids (AAs) at 42 previously reported potential nucleos(t)ide analog resistance (NAr) mutation positions in the RT region were analyzed.

RESULTS

Potential NAr mutations involving 24 positions were found in 79 of the 131 patients (60.3%). Notably, AA substitutions at 2 positions (rt184 and rt204) involved in primary drug resistance and at 2 positions (rt80 and rt180) that functioned as secondary/compensatory mutations were detected in 10 patients (1 CH patient and 9 HCC patients) and 7 patients (1 CH and 6 HCC patients), respectively. The overall mutation frequencies in the HCC patients (3.17%, 96/3024 mutations) were significantly higher than the frequencies in the CH patients (2.09%, 52/2478 mutations) (P = 0.003). In addition, a total of 3 NAr positions, rt80, rt139 and rt204 were found to be significantly related to HCC from treatment naïve Korean patients.

CONCLUSION

Our data showed that naturally occurring NAr mutations in South Korea might contribute to liver disease progression (particularly HCC generation) in chronic patients with genotype C2 infections.

Keywords: Hepatitis B virus, Polymerase, Reverse transcriptase, Potential nucleos(t)ide analog resistance, Chronic hepatitis, Hepatocellular carcinoma

Core tip: To date, naturally occurring mutations in hepatitis B virus (HBV) reverse transcriptase region (RT) in genotype C2-infected patients have rarely been introduced in terms of clinical severity. So, this study characterized the AA substitutions at the aforementioned 42 potential NAr mutation positions in HBV RT sequences from a cohort of 131 Korean treatment-naïve CHB patients with genotype C2 infections. Notably, AA substitutions at positions involved in primary (rt184 and rt204) or secondary drug resistance (rt80 and rt180) were detected in 10 patients [1 CH patient and 9 hepatocellular carcinoma (HCC) patients] and 7 patients (1 CH and 6 HCC patients), respectively. The overall mutation frequencies in the HCC patients (3.17%, 96/3024 mutations) were significantly higher than the frequencies in the CH patients (2.09%, 52/2478 mutations), suggesting that naturally occurring NAr mutations in South Korea might contribute to liver disease progression (particularly HCC generation) in chronic patients with genotype C2 infections. In addition, a total of 3 NAr positions, rt80, rt139 and rt204 were found to be significantly related to HCC from treatment naïve Korean patients.