Chronic hepatitis B virus (HBV) infection is a challenging global health problem. To identify genetic loci involved in chronic HBV infection, we designed a three-phase genome-wide association study in Han Chinese populations. The discovery phase included 951 HBV carriers (cases) and 937 individuals who had naturally cleared HBV infection (controls) and was followed by independent replications with a total of 2,248 cases and 3,051 controls and additional replications with 1,982 HBV carriers and 2,622 controls from the general population. We identified two new loci associated with chronic HBV infection: rs3130542 at 6p21.33 (near HLA-C, odds ratio (OR) = 1.33, P = 9.49 × 10−14) and rs4821116 at 22q11.21 (in UBE2L3, OR = 0.82, P = 1.71 × 10−12). Additionally, we replicated the previously identified associations of HLA-DP and HLA-DQ variants at 6p21.32 with chronic HBV infection. These findings highlight the importance of HLA-C and UBE2L3 in the clearance of HBV infection in addition to HLA-DP and HLA-DQ.

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The authors thank all study subjects, research staff and students who participated in this work and Z. Wang (US National Cancer Institute) for statistical help with imputation. This work was funded by the National Key Basic Research Program (2013CB911400), the project supported by the National Science Foundation for Distinguished Young Scholars of China (81225020), the project supported by the State Key Program of National Natural Science of China (81230067), the Foundation for the Program for New Century Excellent Talents in University (NCET-10-0178), the Author of National Excellent Doctoral Dissertation (201081), the National Natural Science Foundation of China (30800946 and 81072344), the State Key Infectious Disease Project of China (2012ZX10002010 and 2012ZX10002016), the National Major Science & Technology Project (2011ZX10004-902), the National Science Fund for Creative Research Groups (30921006), the National Key Basic Research Program (2013CB910304), a China National High-Tech Research and Development Program grant (2012AA02A515), the Foundation for Distinguished Young Scholars of Jiangsu Province (BK2012042 and BK20130042) and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Author information

Author notes

    • Zhibin Hu
    • , Yao Liu
    • , Xiangjun Zhai
    • , Juncheng Dai
    • , Guangfu Jin
    •  & Li Wang

    These authors contributed equally to this work.


  1. Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Department of Epidemiology & Biostatistics, Nanjing Medical University, Nanjing, China.

    • Zhibin Hu
    • , Yao Liu
    • , Juncheng Dai
    • , Guangfu Jin
    • , Minjie Chu
    • , Juan Wen
    • , Kaipeng Xie
    • , Yisha He
    •  & Hongbing Shen
  2. State Key Laboratory of Reproductive Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.

    • Zhibin Hu
    • , Yao Liu
    • , Juncheng Dai
    • , Guangfu Jin
    • , Minjie Chu
    • , Juan Wen
    • , Kaipeng Xie
    • , Yisha He
    •  & Hongbing Shen
  3. Department of Infectious Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China.

    • Xiangjun Zhai
    • , Liguo Zhu
    •  & Haitao Yang
  4. Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.

    • Li Wang
  5. Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

    • Yuan Yang
    •  & Weiping Zhou
  6. Tumor Biobank, Nantong Tumor Hospital, Nantong, China.

    • Jibin Liu
    •  & Li Liu
  7. National Major Science & Technology Project Executive Office, Zhangjiagang Center for Disease Prevention and Control, Zhangjiagang, China.

    • Guoming Du
    •  & Qungang Wang
  8. National Major Science & Technology Project Executive Office, Taixing Center for Disease Prevention and Control, Taixing, China.

    • Yuchun Zhou
    •  & Minquan Cao
  9. Virus Laboratory, Wuhan Center for Disease Prevention and Control, Wuhan, China.

    • Ying Wang
  10. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.

    • Gangqiao Zhou
  11. Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.

    • Weihua Jia
    •  & Shengping Li
  12. Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Disease, Guangzhou Medical College, Guangzhou, China.

    • Jiachun Lu
  13. Department of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore.

    • Jianjun Liu
  14. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

    • Yongyong Shi
  15. National Innovation Alliance for Hepatitis & Liver Cancer, Second Military Medical University, Shanghai, China.

    • Weiping Zhou


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H.S. and Z.H. directed the study, obtained financial support and were responsible for study design, interpretation of the results and manuscript writing together with W.Z. and Y.S. Z.H. performed overall project management along with Y.L., G.J. and X.Z. and drafted the initial manuscript. J.D. performed statistical analyses along with Y.L. Y.L., M. Chu, J.W., Y.H. and K.X. were responsible for sample processing and managing the genotyping data. Y.Y. and Y.H. were responsible for subject recruitment and sample preparation for the Shanghai samples. X.Z., L.Z., G.D., Q.W., H.Y. and M. Cao were responsible for subject recruitment and sample preparation for the Zhangjiagang and Changzhou samples. X.Z., Y.Z. and J.W. were responsible for subject recruitment and sample preparation for the Taizhou samples. Jibin Liu, L.L. and K.X. were responsible for subject recruitment and sample preparation for the Nantong samples. L.W., G.Z. and Y.W. were responsible for subject recruitment and sample preparation for the Beijing samples. W.J., S.L. and J. Lu were responsible for subject recruitment and sample preparation for the Guangdong samples. Jianjun Liu provided technical and material support. All authors approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Zhibin Hu or Yongyong Shi or Weiping Zhou or Hongbing Shen.

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