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Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma

Abstract

To identify the genetic susceptibility factor(s) for hepatitis C virus–induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2,890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P < 1 × 10−5) in the genome-wide association study were further genotyped in 673 cases and 2,596 controls. We found a previously unidentified locus in the 5′ flanking region of MICA on 6p21.33 (rs2596542, Pcombined = 4.21 × 10−13, odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61) but is significantly associated with progression from CHC to HCC (P = 3.13 × 10−8). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P = 1.38 × 10−13).

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Figure 1: Regional association plot at rs2596542.
Figure 2: Correlation between soluble MICA levels and rs2596542 genotype.
Figure 3: Correlation between soluble MICA and HCV-related diseases.

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Acknowledgements

We would like to thank all the subjects and the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan who donated their DNA for this work. We also thank the technical staff of the Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, and the Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo. This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

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Contributions

K.M. and Y.N. conceived of the study; Y.N., V.K., M.K. and K.M. designed the study; V.K., Y.U., R.M. and N.H. performed genotyping; V.K., Y.N. and K.M. wrote the manuscript; A.T. and N. Kamatani performed quality control at the genome-wide phase; Y.N., K.M., H.N. and M.K. managed DNA and serum samples belonging to BioBank Japan; N. Kato, R.T., M. Otsuka, M. Omata and K.K. managed replication DNA and serum samples; V.K. analyzed the data, performed VNTR genotyping, ELISA and summarized the whole results; Y.N. obtained funding for the study.

Corresponding author

Correspondence to Koichi Matsuda.

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The authors declare no competing financial interests.

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Supplementary Figures 1–10 and Supplementary Tables 1–17. (PDF 1318 kb)

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Kumar, V., Kato, N., Urabe, Y. et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 43, 455–458 (2011). https://doi.org/10.1038/ng.809

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