Original Paper

Putative Association of Fas and FasL Gene Polymorphisms with Clinical Outcomes of Hepatitis B Virus Infection
Yong Jin Jung^a, Yoon Jun Kim^a, Lyoung Hyo Kim^b, Soo Ok Lee^b, Byung Lae Park^b, Hyoung Doo Shin^b, Hyo-Suk Lee<sup>a

a</sup>Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, and
^bDepartment of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Korea

Address of Corresponding Author

Intervirology 2007;50:369-376 (DOI: 10.1159/000109751)

  Key Words

• Fas
• FasL
• Polymorphism
• Hepatitis B virus
• Hepatocellular carcinoma

  Abstract

Objective:Fas/FasL polymorphisms, which are related to apoptosis, might influence the clearance of hepatitis B virus (HBV) infection and the occurrence of hepatocellular carcinoma (HCC). This study was performed to determine whether Fas and FasL promoter polymorphisms are associated with clinical outcome in chronic HBV infection. Methods: A total of 1,095 Korean subjects were prospectively allocated to two different groups: 'the chronic carrier group' (CC; n = 666), who were repeatedly hepatitis B surface antigen (HBsAg)-positive, and 'the spontaneous recovery group' (SR; n = 429), who were HBsAg-negative with antibodies to HBsAg and hepatitis B core antigen. In addition, the CC group was subcategorized into chronic hepatitis and HCC subgroups. Fas promoter polymorphisms at -1377G>A and -670A>G and the FasL promoter polymorphism at -844C>T were analyzed for and the genotype distributions of subjects were compared. Results: There were no significant associations between Fas or FasL promoter polymorphism with the HBV clearance and HBeAg clearance. However, -1377G>A in Fas promoter region showed protective effect to HCC occurrence (RH = 0.70, p = 0.03). Conclusions:Fas-1377G>A polymorphisms might be involved in the pathogenesis of human HCC.

Copyright © 2007 S. Karger AG, Basel

  References

1.

Purcell RH: The discovery of the hepatitis viruses. Gastroenterology 1993;104:955-963.

2.

Fattovich G: Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23:47-58.

3.

Stevens CE, Beasley RP, Tsui J, Lee WC: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 1975;292:771-774.

4.

Lok AS, Lai CL, Wu PC, Wong VC, Yeoh EK, Lin HJ: Hepatitis B virus infection in Chinese families in Hong Kong. Am J Epidemiol 1987;126:492-499.

5.

Cacciola I, Cerenzia G, Pollicino T, Squadrito G, Castellaneta S, Zanetti AR, Mieli-Vergani G, Raimondo G: Genomic heterogeneity of hepatitis B virus (HBV) and outcome of perinatal HBV infection. J Hepatol 2002;36:426-432.

6.

Chisari FV, Ferrari C: Hepatitis B virus immunopathogenesis. Annu Rev Immunol 1995;13:29-60.

7.

Chisari FV: Cytotoxic T cells and viral hepatitis. J Clin Invest 1997;99:1472-1477.

8.

Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, Realdi G, Ruol A: Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-298.

9.

Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S, Hengartner H, Golstein P: Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 1994;265:528-530.

10.

Nagata S: Apoptosis by death factor. Cell 1997;88:355-365.

11.

Suda T, Okazaki T, Naito Y, Yokota T, Arai N, Ozaki S, Nakao K, Nagata S: Expression of the Fas ligand in cells of T cell lineage. J Immunol 1995;154:3806-3813.

12.

Hayashi N, Mita E: Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis. J Viral Hepat 1999;6:357-365.

13.

Hiramatsu N, Hayashi N, Katayama K, Mochizuki K, Kawanishi Y, Kasahara A, Fusamoto H, Kamada T: Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology 1994;19:1354-1359.

14.

Mochizuki K, Hayashi N, Hiramatsu N, Katayama K, Kawanishi Y, Kasahara A, Fusamoto H, Kamada T: Fas antigen expression in liver tissues of patients with chronic hepatitis B. J Hepatol 1996;24:1-7.

15.

Green DR, Evan GI: A matter of life and death. Cancer Cell 2002;1:19-30.

16.

Nagao M, Nakajima Y, Hisanaga M, Kayagaki N, Kanehiro H, Aomatsu Y, Ko S, Yagita H, Yamada T, Okumura K, Nakano H: The alteration of Fas receptor and ligand system in hepatocellular carcinomas: How do hepatoma cells escape from the host immune surveillance in vivo? Hepatology 1999;30:413-421.

17.

Thursz M: Genetic susceptibility in chronic viral hepatitis. Antiviral Res 2001;52:113-116.

18.

Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003;423:293-298.

19.

Huang QR, Morris D, Manolios N: Identification and characterization of polymorphisms in the promoter region of the human Apo-1/Fas (CD95) gene. Mol Immunol 1997;34:577-582.

20.

Wu J, Metz C, Xu X, Abe R, Gibson AW, Edberg JC, Cooke J, Xie F, Cooper GS, Kimberly RP: A novel polymorphic CAAT/enhancer-binding protein element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African-American systemic lupus erythematosus patients. J Immunol 2003;170:132-138.

21.

Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 2005;42:1208-1236.

22.

Hedrick PW: Gametic disequilibrium measures: proceed with caution. Genetics 1987;117:331-341.

23.

Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001;68:978-989.

24.

Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV: Viral clearance without destruction of infected cells during acute HBV infection. Science 1999;284:825-829.

25.

Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, Haussinger D: Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334:1422-1427.

26.

Lee WM: Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745.

27.

Liu CJ, Chen PJ, Lai MY, Lin FY, Wang T, Kao JH, Chen DS: Viral factors correlate with hepatitis B e antigen seroconverson in patients with chronic hepatitis B. Liver Int 2006;26:949-955.

28.

Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, et al: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797-1801.

29.

Muschen M, Warskulat U, Beckmann MW: Defining CD95 as a tumor suppressor gene. J Mol Med 2000;78:312-325.

30.

Gratas C, Tohma Y, Barnas C, Taniere P, Hainaut P, Ohgaki H: Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res 1998;58:2057-2062.

31.

Sun T, Miao X, Zhang X, Tan W, Xiong P, Lin D: Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J Natl Cancer Inst 2004;96:1030-1036.

32.

Zhang X, Miao X, Sun T, Tan W, Qu S, Xiong P, Zhou Y, Lin D: Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer. J Med Genet 2005;42:479-484.

33.

Nada O, Abdel-Hamid M, Ismail A, Shabrawy LE, Sidhom KF, Badawy NM, Ghazal FA, Daly ME, Kafrawy SE, Esmat G, Loffredo CA: The role of the tumor necrosis factor - FasL and HCV in the development of hepatocellular carcinoma. J Clin Virol 2005;34:140-146.

34.

Lee SH, Shin MS, Lee HS, Bae JH, Lee HK, Kim HS, Kim SY, Jang JJ, Joo M, Kang YK, Park WS, Park JY, Oh RR, Han SY, Lee JH, Kim SH, Lee JY, Yoo NJ: Expression of Fas and Fas-related molecules in human hepatocellular carcinoma. Hum Pathol 2001;32:250-256.

35.

Nakamoto Y, Kaneko S, Fan H, Momoi T, Tsutsui H, Nakanishi K, Kobayashi K, Suda T: Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-Fas ligand antibody therapy. J Exp Med 2002;196:1105-1111.

36.

Kim YJ, Lee HS: Single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Intervirology 2005;48:10-15.

37.

Kim YJ, Lee HS, Im JP, Min BH, Kim HD, Jeong JB, Yoon JH, Kim CY, Kim MS, Kim JY, Jung JH, Kim LH, Park BL, Shin HD: Association of transforming growth factor-₁ gene polymorphisms with a hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection. Exp Mol Med 2003;35:196-202.

38.

Shin HD, Park BL, Kim LH, Jung JH, Kim JY, Yoon JH, Kim YJ, Lee HS: Interleukin-10 haplotype associated with increased risk of hepatocellular carcinoma. Hum Mol Genet 2003;12:901-906.

39.

Lieberman HM, LaBrecque DR, Kew MC, Hadziyannis SJ, Shafritz DA: Detection of hepatitis B virus DNA directly in human serum by a simplified molecular hybridization test: comparison to HBeAg/anti-HBe status in HBsAg carriers. Hepatology 1983;3:285-291.

  Author Contacts

Hyo-Suk Lee, MD
Department of Internal Medicine, Seoul National University Hospital
28 Yeongeon-dong, Jongno-gu, Seoul 110-744 (Korea)
Tel. +82 2 745 7557, Fax +82 2 744 8243
E-Mail hsleemd@snu.ac.kr

  Article Information

Y.J.J. and Y.J.K. contributed equally to this work.

Received: March 12, 2007
Accepted after revision: June 25, 2007
Published online: October 15, 2007
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 5, Number of References : 39

  Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 50, No. 5, Year 2007 (Cover Date: October 2007)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300-5526 (print), 1423-0100 (Online)

For additional information: http://www.karger.com/INT

  Drug Dosage / Copyright

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