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Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers

Nature Genetics volume 42, pages 755–758 (2010)Cite this article

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Abstract

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 × 10−18). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

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Figure 1: Regional plots for associations at 1p36.22.

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Acknowledgements

We thank the subjects and their families for participating in this study, and the clinicians, nurses and study coordinators for their contributions. This study was supported in part by grants from Chinese National High-tech Program 2006AA02A412 (G.Z.), Chinese Key Project for Infectious Diseases 2008ZX10002-016 (G.Z.), Chinese National Science Fund for Creative Research Groups Program 30621063 (F.H.) and Beijing Science and Technology NOVA program 2006A54 (G.Z.).

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Author notes

  1. Zhibin Hu, Chen Wu, Ji Qian and Weihua Jia: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China

    Hongxing Zhang, Yun Zhai, Lixia Yu, Wei Yue, Zhifu Wang, Peiyao Li, Yang Zhang, Mi Cai, Xia Xia, Xiumei Zhang, Hao Yang, Wei Qiu, Feng Gong, Fuchu He & Gangqiao Zhou

  2. Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China

    Zhibin Hu & Hongbing Shen

  3. Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Chen Wu & Dongxin Lin

  4. MOE Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Ji Qian & Jingmin Yang

  5. State Key Laboratory of Oncology in Southern China, Guangzhou, Guangdong, China

    Weihua Jia, Yunfei Yuan & Yi-Xin Zeng

  6. Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China

    Weihua Jia & Yi-Xin Zeng

  7. Cancer Institute of Guangxi, Nanning, Guangxi, China

    Fuchao Ma, Wenfeng Huang, Ying Cui & Weimin Xie

  8. Liver Cancer Institute at Fusui County, Guangxi, China

    Renxiang Liang & Zhongliang Wei

  9. Disease Prevention and Control Center at Haimen County, Jiangsu, China

    Xinsen Yu

  10. Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China

    Minshan Chen

  11. Institute of Biomedical Sciences, Fudan University, Shanghai, China

    Fuchu He

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  1. Hongxing Zhang
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Contributions

G.Z. and F.H. were the overall GWAS study principal investigators who conceived the study and obtained financial support. F.H., G.Z. and H.Z. designed the study. Y.C., W.X., R.L., Z.W., F.M. and W.H. were responsible for recruitment of Guangxi subjects, phenotype collection and biological sample collection and preparation. W.J., Y.Y., M.C. and Y.-X.Z. were responsible for recruitment of Guangdong subjects, phenotype collection and biological sample collection and preparation. Z.H., H.S. and X.Y. were responsible for recruitment of Jiangsu subjects, phenotype collection and biological sample collection and preparation. J.Y. and J.Q. were responsible for recruitment of Shanghai subjects, phenotype collection and biological sample collection and preparation. C.W. and D.L. were responsible for recruitment of Beijing subjects, phenotype collection and biological sample collection and preparation. Y.Z., L.Y., P.L., Z.W., F.M., W.H., W.Y., M.C., X.Z., W.Q., H.Y. and H.Z. performed genotyping in the replication stage. X.X. helped to manage genotype data. F.G., Y.Z. and F.M. conducted functional experiments. G.Z. and H.Z. conducted sample selection and data management, performed statistical analyses, interpreted results and wrote the manuscript.

Corresponding authors

Correspondence to Fuchu He or Gangqiao Zhou.

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The authors declare no competing financial interests.

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Zhang, H., Zhai, Y., Hu, Z. et al. Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet 42, 755–758 (2010). https://doi.org/10.1038/ng.638

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