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Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers

Abstract

Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, Pcombined = 1.27 × 10−13, odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 × 10−14, odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection.

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Figure 1: Case-control association plots and linkage disequilibrium (LD) map and genomic structure of the DEPDC5 region in chromosome 22q12.2–3.

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References

  1. Yang, J.D. & Roberts, L.R. Hepatocellular carcinoma: a global view. Nat. Rev. Gastroenterol. Hepatol. 7, 448–458 (2010).

    Article  Google Scholar 

  2. Barrera, J.M. et al. Persistent hepatitis C viremia after acute self-limiting posttransfusion hepatitis C. Hepatology 21, 639–644 (1995).

    Article  CAS  Google Scholar 

  3. Welzel, T.M. et al. Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology 49, 1847–1858 (2009).

    Article  CAS  Google Scholar 

  4. Yoshida, H. et al. Interferon therapy reduces the risk for hepatocellular carcinoma. Ann. Intern. Med. 131, 174–181 (1999).

    Article  CAS  Google Scholar 

  5. Kiyosawa, K. et al. Hepatocellular carcinoma: recent trends in Japan. Gastroenterology 127, S17–S26 (2004).

    Article  Google Scholar 

  6. Taura, N. et al. Aging of patients with hepatitis C virus-associated hepatocellular carcinoma: long-term trends in Japan. Oncol. Rep. 16, 837–843 (2006).

    PubMed  Google Scholar 

  7. Miki, D. et al. Clinicopathological features of elderly patients with hepatitis C virus-related hepatocellular carcinoma. J. Gastroenterol. 43, 550–557 (2008).

    Article  Google Scholar 

  8. Takata, A. et al. HCC develops even in the early stage of chronic liver disease in elderly patients with HCV infection. Int. J. Mol. Med. 26, 249–256 (2010).

    Article  CAS  Google Scholar 

  9. Yuen, M.F., Hou, J.L. & Chutaputti, A. Hepatocellular carcinoma in the Asia pacific region. J. Gastroenterol. Hepatol. 24, 346–353 (2009).

    Article  Google Scholar 

  10. Manns, M.P. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965 (2001).

    Article  CAS  Google Scholar 

  11. Zhang, H. 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).

    Article  CAS  Google Scholar 

  12. Ura, S. et al. Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology 49, 1098–1112 (2009).

    Article  CAS  Google Scholar 

  13. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

    Article  Google Scholar 

  14. Yamauchi, T. et al. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A–C2CD4B. Nat. Genet. 42, 864–868 (2010).

    Article  CAS  Google Scholar 

  15. Ono, E. et al. Platelet count reflects stage of chronic hepatitis C. Hepatol. Res. 15, 192–200 (1999).

    Article  Google Scholar 

  16. Poynard, T. & Bedossa, P. Age and platelet count: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. J. Viral Hepat. 4, 199–208 (1997).

    Article  CAS  Google Scholar 

  17. Forns, X. et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 36, 986–992 (2002).

    Article  Google Scholar 

  18. Wai, C.T. et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 38, 518–526 (2003).

    Article  Google Scholar 

  19. Pohl, A. et al. Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am. J. Gastroenterol. 96, 3142–3146 (2001).

    Article  CAS  Google Scholar 

  20. Seng, T.J. et al. Complex chromosome 22 rearrangements in astrocytic tumors identified using microsatellite and chromosome 22 tile path array analysis. Genes Chromosom. Cancer 43, 181–193 (2005).

    Article  CAS  Google Scholar 

  21. Kharrat, A. et al. Conformational stability studies of the pleckstrin DEP domain: definition of the domain boundaries. Biochim. Biophys. Acta 1385, 157–164 (1998).

    Article  CAS  Google Scholar 

  22. Harada, Y. et al. Cell-permeable peptide DEPDC1–ZNF224 interferes with transcriptional repression and oncogenicity in bladder cancer cells. Cancer Res. 70, 5829–5839 (2010).

    Article  CAS  Google Scholar 

  23. Kanehira, M. et al. Involvement of upregulation of DEPDC1 (DEP domain containing 1) in bladder carcinogenesis. Oncogene 26, 6448–6455 (2007).

    Article  CAS  Google Scholar 

  24. The general rules for the clinical and pathological study of primary liver cancer. Liver Cancer Study Group of Japan 3rd English edn. (Kanehara & Co., Ltd., Tokyo, Japan, 2010).

  25. Yamaguchi-Kabata, Y. et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am. J. Hum. Genet. 83, 445–456 (2008).

    Article  CAS  Google Scholar 

  26. Ohnishi, Y. et al. A high throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  Google Scholar 

  27. Nam, J.M. A simple approximation for calculating sample sizes for detecting linear trend in proportions. Biometrics 43, 701–705 (1987).

    Article  CAS  Google Scholar 

  28. Margolin, B.H. Test for trend in proportions. in Encyclopedia of statistical sciences. (eds. Klotz, S. & Johnson, N.L.) 334–336 (John Wiley & Sons, Inc., New York, New York, USA, 1988).

  29. Menashe, I., Rosenberg, P.S. & Chen, B.E. PGA: Power calculator for case-control genetic association analyses. BMC Genet. 9, 36 (2008).

    Article  Google Scholar 

  30. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  31. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the subjects who agreed to participate in this study. We also thank the team members at Toranomon Hospital, Sapporo Kosei General Hospital, Hiroshima University Hospital and Hiroshima Liver Study Group for clinical sample collection. We thank T. Yokogi, Y. Hayashida and K. Izumoto for technical assistance, J. Sakamiya for clerical assistance and other members of the RIKEN Center for Genomic Medicine and Hiroshima University for assistance with various aspects of this study.

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Authors

Contributions

K.C. conceived the study. D.M., H.O. and K.C. designed the study. D.M. and H.O. performed genotyping. D.M., H.O., C.N.H. and K.C. wrote the manuscript. T.M., T.T., M.K. and N.K. performed data analysis at the genome-wide phase. H. Abe and T.Y. performed functional analyses. H. Aikata, K.I., H.K., J.T. and K.C. managed DNA samples. D.M., H.O. and K.C. summarized the whole results. Y.N., N.K. and K.C. obtained funding for the study.

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Correspondence to Kazuaki Chayama.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6 and Supplementary Tables 1–12. (PDF 820 kb)

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Miki, D., Ochi, H., Hayes, C. et al. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet 43, 797–800 (2011). https://doi.org/10.1038/ng.876

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