Abstract

To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).

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Acknowledgements

We thank all the subjects who participated in this study. We also thank Y. Shi and L. He from Bio-X Institutes of Shanghai Jiao Tong University for helping with data analysis of typical Chinese population control subjects, and L. Jin, Y. Zhong, H.-H. Wang and W.-Y. Yan from the School of Life Sciences of Fudan University and H.-B. Shu from College of Life Sciences of Wuhan University for suggestions on this study. The study is supported by the National Natural Science Foundation of China for Creative Research Groups (30024001 to L.Y.), the National Key Sci-Tech Special Project of China (2013ZX10002010 and 2008ZX10002-020 to L.Y.), the Project of the Shanghai Municipal Science and Technology Commission (to L.Y.), the National Natural Science Foundation of China (31071193 to L.Y. and 31100895 to D.-K.J.), Director Foundation of the State Key Laboratory of Genetic Engineering (to L.Y.), the Fund from X.-J. Qu and Chang-An Capital of Beijing (to L.Y.), the Fund from S.-J. Yan and Tianying S.T. Group of Jiangsu (to L.Y.), MOE Foundation of Cheung Kong Scholars Program (to J.L. and Q.Y.), an intramural research grant from Huashan Hospital, Fudan University (to J.X.) and an intramural research grant from Fudan-VARI Center for Genetic Epidemiology, Fudan University (to J.X.). This work is partly funded by the National Natural Science Foundation of China (30800946 to H.S.), Foundation for the Author of National Excellent Doctoral Dissertation (201081 to H.S.), the Program for New Century Excellent Talents in University (NCET-10-0178 to H.S.), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (to H.S.).

Author information

Author notes

    • De-Ke Jiang
    • , Jielin Sun
    • , Guangwen Cao
    • , Yao Liu
    •  & Dongxin Lin

    These authors contributed equally to this work.

    • Jianfeng Xu
    •  & Long Yu

    These authors jointly directed this work.

Affiliations

  1. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.

    • De-Ke Jiang
    • , Wei-Hua Ren
    • , Xiao-Pin Ma
    • , Wei Jiang
    • , Hui-Xing Huang
    • , Dan Wang
    • , Li-Sha Tang
    • , Bo Peng
    • , Hao Cai
    • , Ting-Ting Liu
    • , Ping Zhou
    • , Bo Wan
    • , He-Xi Ge Sai-Yin
    • , Jun Liu
    • , Qing Yi
    •  & Long Yu
  2. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Jielin Sun
    • , Zhong Wang
    • , Sha Tao
    • , S Lilly Zheng
    •  & Jianfeng Xu
  3. Department of Epidemiology, Second Military Medical University, Shanghai, China.

    • Guangwen Cao
    • , Jianhua Yin
    •  & Hongwei Zhang
  4. Ministry of Education Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.

    • Yao Liu
    • , Zhibin Hu
    •  & Hongbing Shen
  5. Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.

    • Yao Liu
    • , Zhibin Hu
    •  & Hongbing Shen
  6. State Key Laboratory of Reproductive Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.

    • Yao Liu
    • , Zhibin Hu
    •  & Hongbing Shen
  7. Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Dongxin Lin
    • , Chen Wu
    • , Jiang Chang
    •  & Kan Zhai
  8. Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.

    • Yu-Zhen Gao
  9. Department of Surgery, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, China.

    • Wei-Hua Ren
    •  & Yan Pei
  10. Department of Pathology, Youjiang Medical College for Nationalities, Baise, China.

    • Xi-Dai Long
    •  & Yuan-Feng Zhou
  11. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.

    • Hongxing Zhang
    • , Yun Zhai
    • , Xiaoli Gu
    •  & Gangqiao Zhou
  12. Qidong Liver Cancer Institute, Qidong, China.

    • Tao-Yang Chen
    • , Pei-Xin Lu
    •  & Neng-Jin Wang
  13. Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.

    • Yong Gao
    • , Aihua Tan
    •  & Zengnan Mo
  14. Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.

    • Yong Gao
    • , Aihua Tan
    •  & Zengnan Mo
  15. Fudan-VARI Center for Genetic Epidemiology, Fudan University, Shanghai, China.

    • Yong Gao
    • , Hongjie Yu
    • , Pengyin Zhang
    • , Fang Liu
    • , Xiaoling Lin
    •  & Jianfeng Xu
  16. Institute of Dermatology, Anhui Medical University, Hefei, China.

    • Liang-Dan Sun
    • , Xian-Bo Zuo
    • , Yang Li
    •  & Xue-Jun Zhang
  17. Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, China.

    • Liang-Dan Sun
    • , Xian-Bo Zuo
    • , Yang Li
    •  & Xue-Jun Zhang
  18. State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China.

    • Liang-Dan Sun
    • , Xian-Bo Zuo
    • , Yang Li
    •  & Xue-Jun Zhang
  19. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Ji-Rong Long
    • , Wei Zheng
    •  & Xiao-Ou Shu
  20. Liver Cancer Institute, Fudan University, Shanghai, China.

    • Lun-Xiu Qin
    • , Jia Fan
    •  & Yin-Kun Liu
  21. Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

    • Lun-Xiu Qin
    • , Jia Fan
    •  & Yin-Kun Liu
  22. Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China.

    • Li Liu
  23. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Jun Liu
  24. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Qing Yi
  25. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Qing Yi
  26. Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Qing Yi
  27. Shanghai Cancer Institute, Shanghai, China.

    • Yongbing Xiang
  28. School of Public Health, Shanghai Jiaotong University, Shanghai, China.

    • Rong Shi
  29. Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.

    • Qiang Ding
    •  & Jianfeng Xu
  30. Unit of Statistical Genomics, Division of Intramural Research Program, National Institute of Mental Health, US National Institutes of Health, Bethesda, Maryland, USA.

    • Yin Yao Shugart
  31. Institute of Biomedical Science, Fudan University, Shanghai, China.

    • Long Yu

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Contributions

L.Y. and J.X. designed and directed the study. D.-K.J. carried out overall project management. D.-K.J., X.-P.M., H.-X.H., D.W., L.-S.T., B.P., T.-T.L., P. Zhou, B.W. and H.-X.G.S.-Y. managed DNA samples. S.L.Z., D.-K.J., P. Zhang, X.-P.M. and H.-X.H. did genotyping. J.S., Z.W., D.-K.J., H.Y. and Y.Y.S. conducted data analysis. W.J., D.-K.J., X.-P.M. and H.C. did functional analyses. D.-K.J., Z.W., J.X. and L.Y. summarized results. D.-K.J., J.X. and J.S. wrote the manuscript. The following authors from the various collaborating groups carried out assembly of case-control series in their respective regions and collected data and samples: G.C., J.Y. and Hongwei Zhang in Shanghai, Y. Liu, H.S., L.L. and Z.H. in Nanjing; D.L., C.W., J.C. and K.Z. in Beijing; Y.-Z.G. in Suzhou; W.-H.R. and Y.P. in Luoyang; X.-D.L. and Y.-F.Z. in Baise; G.Z., Hongxing Zhang, Y.Z. and X.G. in Fusui; and T.-Y.C. and P.-X.L. in Qidong. The following authors collected partial control subjects in their respective regions: Z.M., Y.G. and A.T. in Guangxi Province. The following authors provided genotype data of typical Chinese population control subjects: X.-J.Z., L.-D.S., X.-B.Z., Y. Li, X.-O.S., W.Z., J.-R.L., Y.X., R.S., F.L., X.L, S.T., Q.D. and J.X. The following authors collected tissue samples of HCC cases: T.-Y.C. and N.-J.W. (major part); L.-X.Q., J.F. and Y.-K.L. (minor part). L.Y., J.X., J.L., Q.Y., D.-K.J. and H.S. obtained funding for the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jianfeng Xu or Long Yu.

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https://doi.org/10.1038/ng.2483

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