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

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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.).

Author information

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.

Correspondence to Fuchu He or Gangqiao Zhou.

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The authors declare no competing financial interests.

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