Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Identification of additional EHMT2 variant associated with the risk of chronic hepatitis B by GWAS follow-up study

Genes & Immunity volume 20, pages 1–9 (2019)Cite this article

Subjects

Abstract

Chronic hepatitis B (CHB) is a precursor to liver cirrhosis and hepatocellular carcinoma, caused by a Hepatitis B viral infection. Genome-wide association studies (GWASs) have been conducted to find genes associated with CHB risk. In previous GWAS, EHMT2 was identified as one of the susceptibility genes for CHB. To further characterize this association and discover possible causal variants, we conducted an additional association study. A total of 11 EHMT2 single-nucleotide polymorphisms (SNP) were selected and genotyped in 3902 subjects (1046 CHB patients and 2856 controls). An additional eight imputed SNPs were also included in further analysis. As a result, rs35875104 showed a strong association with the CHB, along with the previously reported genetic marker for CHB risk, rs652888 (odds ratio (OR) = 0.53, P = 2.20 × 10−8 at rs35875104 and OR = 1.58, P = 9.90 × 10−12 at rs652888). In addition, linkage disequilibrium and conditional analysis identified one SNP (rs35875104) as a novel genetic marker for CHB susceptibility. The GRSs (genetic risk scores) were calculated to visualize the combined genetic effects of all known CHB-associated loci, including EHMT2 rs35875104, which was additionally identified in this study. The findings from the present study may be useful for further understanding of the genetic etiology of CHB.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Kane MA. [World-wide epidemiology of hepatitis B]. Soz Praventivmed. 1998;43(Suppl 1):S98–100 S24-6.

    Article  Google Scholar 

  2. Chu CM, Karayiannis P, Fowler MJ, Monjardino J, Liaw YF, Thomas HC. Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology. 1985;5:431–4.

    Article  CAS  PubMed  Google Scholar 

  3. Hadziyannis SJ, Vassilopoulos D, Hepatitis B e antigen-negative chronic hepatitis B. Hepatology.2001;34:617–24.

    Article  CAS  PubMed  Google Scholar 

  4. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–83.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, et al A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet. 2009;41:591–5.

    Article  CAS  PubMed  Google Scholar 

  6. Mbarek H, Ochi H, Urabe Y, Kumar V, Kubo M, Hosono N, et al A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. Hum Mol Genet. 2011;20:3884–92.

    Article  CAS  PubMed  Google Scholar 

  7. Liu L, Li J, Yao J, Yu J, Zhang J, Ning Q, et al A genome-wide association study with DNA pooling identifies the variant rs11866328 in the GRIN2A gene that affects disease progression of chronic HBV infection. Viral Immunol. 2011;24:397–402.

    Article  CAS  PubMed  Google Scholar 

  8. Kim YJ, Kim HY, Lee JH, Yu SJ, Yoon JH, Lee HS, et al. A genome-wide association study identified new variants associated with the risk of chronic hepatitis B. Hum Mol Genet. 2013;22:4233–8.

    Article  CAS  PubMed  Google Scholar 

  9. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19:187–91.

    Article  CAS  PubMed  Google Scholar 

  10. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33:245–54.

    Article  CAS  PubMed  Google Scholar 

  11. Cebrian A, Pharoah PD, Ahmed S, Ropero S, Fraga MF, Smith PL, et al. Genetic variants in epigenetic genes and breast cancer risk. Carcinogenesis. 2006;27:1661–9.

    Article  CAS  PubMed  Google Scholar 

  12. de Vogel S, Wouters KA, Gottschalk RW, van Schooten FJ, de Goeij AF, de Bruine AP, et al. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2009;18:3086–96.

    Article  PubMed  Google Scholar 

  13. Lee SH, Kim J, Kim WH, Lee YM. Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene. 2009;28:184–94.

    Article  CAS  PubMed  Google Scholar 

  14. Chen MW, Hua KT, Kao HJ, Chi CC, Wei LH, Johansson G, et al. H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010;70:7830–40.

    Article  CAS  PubMed  Google Scholar 

  15. Mann DA. Epigenetics in liver disease. Hepatology. 2014;60:1418–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Son HJ, Kim JY, Hahn Y, Seo SB. Negative regulation of JAK2 by H3K9 methyltransferase G9a in leukemia. Mol Cell Biol. 2012;32:3681–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dong C, Wu Y, Yao J, Wang Y, Yu Y, Rychahou PG, et al. G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J Clin Invest. 2012;122:1469–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yuan Y, Tang AJ, Castoreno AB, Kuo SY, Wang Q, Kuballa P, et al. Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. Cell Death Dis. 2013;4:e690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hung SY, Lin HH, Yeh KT, Chang JG. Histone-modifying genes as biomarkers in hepatocellular carcinoma. Int J Clin Exp Pathol. 2014;7:2496–507.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev. 2002;12:198–209.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Q, Lei X, Lu H. Alterations of epigenetic signatures in hepatocyte nuclear factor 4alpha deficient mouse liver determined by improved ChIP-qPCR and (h)MeDIP-qPCR assays. PLoS ONE. 2014;9:e84925.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yu X, Mertz JE. Distinct modes of regulation of transcription of hepatitis B virus by the nuclear receptors HNF4alpha and COUP-TF1. J Virol. 2003;77:2489–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jiang DK, Ma XP, Yu H, Cao G, Ding DL, Chen H, et al. Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B. Hepatology. 2015;62:118–28.

    Article  CAS  PubMed  Google Scholar 

  24. Posuwan N, Payungporn S, Tangkijvanich P, Ogawa S, Murakami S, Iijima S, et al. Genetic association of human leukocyte antigens with chronicity or resolution of hepatitis B infection in thai population. PLoS ONE. 2014;9:e86007.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.

    Article  CAS  PubMed  Google Scholar 

  26. Cheong HS, Lee JH, Yu SJ, Yoon JH, Lee HS, Cheong JY, et al. Association of VARS2-SFTA2 polymorphisms with the risk of chronic hepatitis B in a Korean population. Liver Int. 2015;35:1934–40.

    Article  CAS  PubMed  Google Scholar 

  27. Fava C, Sjogren M, Olsson S, Lovkvist H, Jood K, Engstrom G, et al. A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study. Eur J Hum Genet. 2015;23:969–74.

    Article  CAS  PubMed  Google Scholar 

  28. Zhou XJ, Qi YY, Hou P, Lv JC, Shi SF, Liu LJ, et al. Cumulative effects of variants identified by genome-wide association studies in IgA nephropathy. Sci Rep. 2014;4:4904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.

    Article  CAS  PubMed  Google Scholar 

  30. Guerrieri F, Belloni L, Pediconi N, Levrero M. Molecular mechanisms of HBV-associated hepatocarcinogenesis. Semin Liver Dis. 2013;33:147–56.

    Article  CAS  PubMed  Google Scholar 

  31. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol. 2006;21:15–21.

    Article  CAS  PubMed  Google Scholar 

  32. Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res. 2007;37:974–83.

    Article  CAS  PubMed  Google Scholar 

  33. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    Article  CAS  PubMed  Google Scholar 

  35. Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5(6):e1000529.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68(4):978–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the patients and their parents without whom this study would not have been possible. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI16C1074, No. A101023); Korea Science and Engineering Foundation (KOSEF), funded by the Korean government (MEST; No. 2011-0004453); a Sogang University Research Grant for 2011 (SRF-201114006.01); and the SNUH Research Fund (04-2016-0300).

Author contributions

Conceived and designed the experiments: Y.J.K. and H.D.S. Performed the experiments: J.G.S., H.S.C., J.Y.K., S.N., and L.H.K. Analyzed the data: J.G.S., H.S.C., and H.D.S. Provided and cared for study patients: J.H.L., S.J.Y., J.H.Y., J.Y.C., S.W.C., N.H.P., and Y.J.K. Contributed to the writing of the manuscript: J.G.S., Y.J.K., and H.D.S.

Author information

Authors and Affiliations

  1. Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea

    Joong-Gon Shin, Jason Yongha Kim, Suhg Namgoong & Hyoung Doo Shin

  2. Research Institute for Basic Science, Sogang University, Seoul, 121-742, Republic of Korea

    Joong-Gon Shin & Hyoung Doo Shin

  3. Department of Genetic Epidemiology, SNP Genetics, Sogang University, Inc., Taihard building 1007, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea

    Hyun Sub Cheong, Suhg Namgoong, Lyoung Hyo Kim & Hyoung Doo Shin

  4. Department of Internal Medicine and Liver Research Institute, Seoul National University, 28 Yungun-dong, Chongro-Gu, Seoul, 110-744, Republic of Korea

    Jeong-Hoon Lee, Su Jong Yu, Jung-Hwan Yoon & Yoon Jun Kim

  5. Department of Internal Medicine, Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 156-707, Republic of Korea

    Jae Youn Cheong

  6. Department of Gastroenterology, Ajou University School of Medicine, San-5 Wonchon-dong, Youngtong-gu, Suwon, 442-721, Republic of Korea

    Sung Won Cho

  7. Department of Internal Medicine, Ulsan University Hospital, 877 Bangeojin Sunhwan-doro, Dong-gu, Ulsan, 682-714, Republic of Korea

    Neung Hwa Park

Authors
  1. Joong-Gon Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun Sub Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason Yongha Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeong-Hoon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Su Jong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jung-Hwan Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jae Youn Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sung Won Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Neung Hwa Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Suhg Namgoong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lyoung Hyo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoon Jun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hyoung Doo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yoon Jun Kim or Hyoung Doo Shin.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, JG., Cheong, H.S., Kim, J.Y. et al. Identification of additional EHMT2 variant associated with the risk of chronic hepatitis B by GWAS follow-up study. Genes Immun 20, 1–9 (2019). https://doi.org/10.1038/s41435-017-0004-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-017-0004-x

This article is cited by

Search

Advanced search

Quick links