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New Gene Variants Associated with the Risk of Chronic HBV Infection

  • RESEARCH ARTICLE
  • Published:
Virologica Sinica

Abstract

Some patients with chronic hepatitis B virus (HBV) infection failed to clear HBV, even persistently continue to produce antibodies to HBV. Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV. The first stage involved genome wide exome sequencing of 101 cases (HBsAg plus anti-HBs positive) compared with 102 control patients (anti-HBs positive, HBsAg negative). Over 80% of individual sequences displayed 20 × sequence coverage. Adapters, uncertain bases > 10% or low-quality base calls (> 50%) were filtered and compared to the human reference genome hg19. In the second stage, 579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage. Although there were no significant associated gene variants in the first stage, two significant gene associations were discovered when the two stages were assessed in a combined analysis. One association showed rs506121-“T” allele [within the dedicator of cytokinesis 8 (DOCK8) gene] was higher in chronic HBV infection group than that in clearance group (P = 0.002, OR = 0.77, 95% CI [0.65, 0.91]). The second association involved rs2071676—A allele within the Carbonic anhydrase (CA9) gene that was significantly elevated in chronic HBV infection group compared to the clearance group (P = 0.0003, OR = 1.35, 95% CI [1.15, 1.58]). Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.

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Abbreviations

ALT:

Alanine transaminase

anti-HAV:

Antibody to hepatitis A virus

anti-HBc:

Antibody to hepatitis B core antigen

anti-HBe:

Antibody to hepatitis B e antigen

anti-HBs:

Antibody to hepatitis B surface antigen

anti-HCV:

Antibody to hepatitis C virus

anti-HDV:

Antibody to hepatitis D virus

anti-HEV:

Antibody to hepatitis E virus

CA9 :

Carbonic anhydrase 9

CHB:

Chronic hepatitis B

DNA:

Deoxyribonucleic acid

DOCK8 :

Dedicator of cytokinesis 8

DP:

Double positive

ELISA:

Enzyme-linked immunosorbent assay

GWAS:

Genome wide association study

HBeAg:

Hepatitis B e antigen

HBsAg:

Hepatitis B surface antigen

HBV:

Hepatitis B virus

HBx:

Hepatitis B x protein

HCC:

Hepatocellular carcinoma

HDV:

Hepatitis D virus

HEV:

Hepatitis E virus

IgM:

Immunoglobulin M

LLOD:

Lower limit of detection

PCR:

Polymerase chain reaction

SD:

Standard deviation

SP:

Single positive

TOF:

Time of flight mass spectrometry

WES:

Whole exome sequencing

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Acknowledgements

This study was supported by grant from the International Science & Technology Cooperation Program of China (No. 2014DFR31200), the National Infrastructure of Chinese Genetic Resources (YCZYPT [2017]01-6), federal funds from the National Cancer Institute, National Institutes of Health, USA (No. N01-CO-12400), and the National Natural Science Foundation of China (No. 30671855).

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Author notes

  1. Mengjie Fan, Jing Wang and Sa Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China

    Mengjie Fan, Sa Wang, Hongli Xi, Yanyan Yu & Zheng Zeng

  2. Department of Medical Genetics and Development Biology, School of Medical Basic, Capital Medical University, Beijing, 100069, China

    Jing Wang

  3. Center for Genetics, National Research Institute for Family Planning, Beijing, 100081, China

    Jing Wang, Tengyan Li, Hong Pan & Binbin Wang

  4. BGI-Shenzhen, Shenzhen, 518083, China

    Hankui Liu, Huifang Xu & Jianguo Zhang

  5. BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China

    Hankui Liu, Huifang Xu & Jianguo Zhang

  6. Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, Russia, 197101

    Daria V. Zhernakova & Stephen J. O’Brien

  7. Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Ft Lauderdale, FL, 33004, USA

    Stephen J. O’Brien

  8. Department of Laboratory Medicine, Peking University First Hospital, Beijing, 100034, China

    Zhenru Feng & Le Chang

  9. The Fifth Hospital of Shijiazhuang, Shijiazhuang, 050024, China

    Erhei Dai & Jianhua Lu

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  1. Mengjie Fan
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  2. Jing Wang
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  3. Sa Wang
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Contributions

ZZ, BBW and JGZ designed the study. MJF, SW, JW, TYL, HP, ZRF, LC, EHD, JHL, HLX and YYY collected samples and analyzed data. MJF, SW, JW, JGZ, BBW and ZZ analyzed and interpreted the data with the assistance of HKL, HFX, DVZ, and SJO. MJF and JW wrote the manuscript. ZZ revised and approved the final manuscript. All authors had full access to the final version of the report and agreed to the submission.

Corresponding authors

Correspondence to Jianguo Zhang, Binbin Wang or Zheng Zeng.

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Animal and Human Rights Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with 1964 Helsinki declaration and later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Peking University First Hospital and the Fifth Hospital of Shijiazhuang. Before entering this research group, all the subjects had signed an informed consent. This study does not contain any studies with animals performed by any of the authors.

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Fan, M., Wang, J., Wang, S. et al. New Gene Variants Associated with the Risk of Chronic HBV Infection. Virol. Sin. 35, 378–387 (2020). https://doi.org/10.1007/s12250-020-00200-x

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