J Korean Med Sci.  2007 Jun;22(3):529-535. 10.3346/jkms.2007.22.3.529.

RANTES, MCP-1, CCR2, CCR5, CXCR1 and CXCR4 Gene Polymorphisms are not Associated with the Outcome of Hepatitis B Virus Infection: Results from a Large Scale Single Ethnic Population

• Cheong JY
• Cho SW
• Choi JY
• Lee JA
• Kim MH
• Lee JE
• Hahm KB
• Kim JH

• KMID: 1778366
• DOI: http://doi.org/10.3346/jkms.2007.22.3.529

Abstract

Recovery from hepatitis B virus (HBV) infection depends on the cellular immune responses. Chemokines and their receptors play significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of genes for the chemokines and their receptors. Between March 2002 and February 2004, a total of 957 single ethnic Korean patients were enrolled into two different groups; "HBV clearance group" (n=350), who have recovered from HBV infection, and "HBV persistence group" (n=607), who were repeatedly HBsAg-positive. The HBV persistence group was subdivided into "inactive carrier" and "HBV progression group (chronic hepatitis and cirrhosis)". We assessed polymorphisms in regulated and normal T-cell expressed and secreted (RANTES) at position -403, monocyte chemoattractant protein-1 (MCP-1) at position -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T and CXCR4 I138I using single primer extension assay. Genotype distributions of the "HBV clearance versus persistence group" and "inactive carrier versus HBV progression group" were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with RANTES -403, MCP-1 -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T, and CXCR4 I138I polymorphisms. In addition, no association of analyzed SNPs with HBV disease progression was found.

Keyword

Hepatitis B; Single Nucleotide Polymorphism (SNP); Chemokines; Chemokine Receptors

MeSH Terms

Chemokine CCL2/*genetics
Chemokine CCL5/*genetics
Disease Progression
Genotype
Hepatitis B/ethnology/*genetics/*therapy
Hepatitis B virus/metabolism
Humans
Korea
*Polymorphism, Genetic
Receptors, CCR2
Receptors, CCR5/*genetics
Receptors, CXCR4/*genetics
Receptors, Chemokine/*genetics
Receptors, Interleukin-8A/*genetics
Regression Analysis
Treatment Outcome

Reference

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

2. Coursaget P, Yvonnet B, Chotard J, Vincelot P, Sarr M, Diouf C, Chiron JP, Diop-Mar I. Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol. 1987. 22:1–5.

3. Tassopoulos NC, Papaevangelou GJ, Sjogren MH, Roumeliotou-Karayannis A, Gerin JL, Purcell RH. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology. 1987. 92:1844–1850.

4. Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM. Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology. 2000. 31:1371–1373.

5. Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, Tur-Kaspa R, Klein T. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol. 2003. 98:144–150.

6. Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenefelde KH, Rittner C. A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol. 1998. 111:579–582.

7. Kim YJ, Lee HS, Yoon JH, Kim CY, Park MH, Kim LH, Park BL, Shin HD. Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection. Hum Mol Genet. 2003. 12:2541–2546.

8. 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.

9. Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV. Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med. 1995. 332:1065–1069.

10. Cheong JY, Cho SW, Chung SG, Lee JA, Yeo M, Wang HJ, Lee JE, Hahm KB, Kim JH. Genetic Polymorphism of Interferon-gamma, Interferon-gamma Receptor, and Interferon Regulatory Factor-1 Genes in Patients with Hepatitis B Virus Infection. Biochem Genet. 2006. 44:246–255.

11. Cheong JY, Cho SW, Hwang IL, Yoon SK, Lee JH, Park CS, Lee JE, Hahm KB, Kim JH. Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-alpha gene promoter polymorphisms. J Gastroenterol Hepatol. 2006. 21:1163–1169.

12. Borish LC, Steinke JW. 2. Cytokines and chemokines. J Allergy Clin Immunol. 2003. 111:S460–S475.

13. Strieter RM, Standiford TJ, Huffnagle GB, Colletti LM, Lukacs NW, Kunkel SL. "The good, the bad, and the ugly." The role of chemokines in models of human disease. J Immunol. 1996. 156:3583–3586.

14. Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996. 35:3362–3367.

15. An P, Nelson GW, Wang L, Donfield S, Goedert JJ, Phair J, Vlahov D, Buchbinder S, Farrar WL, Modi W, O'Brien SJ, Winkler CA. Modulating influence on HIV/AIDS by interacting RANTES gene variants. Proc Natl Acad Sci USA. 2002. 99:10002–10007.

16. Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B. Monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3 are major attractants for human CD4+ and CD8+ T lymphocytes. Faseb J. 1994. 8:1055–1060.

17. Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, Arrighi MC, Pinzani M, Laffi G, Montalto P, Gentilini P. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology. 1999. 29:140–148.

18. Rovin BH, Lu L, Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem Biophys Res Commun. 1999. 259:344–348.

19. Muhlbauer M, Bosserhoff AK, Hartmann A, Thasler WE, Weiss TS, Herfarth H, Lock G, Scholmerich J, Hellerbrand C. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. Gastroenterology. 2003. 125:1085–1093.

20. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996. 381:667–673.

21. Woitas RP, Ahlenstiel G, Iwan A, Rockstroh JK, Brackmann HH, Kupfer B, Matz B, Offergeld R, Sauerbruch T, Spengler U. Frequency of the HIV-protective CC chemokine receptor 5-Delta32/Delta32 genotype is increased in hepatitis C. Gastroenterology. 2002. 122:1721–1728.

22. Kurihara T, Warr G, Loy J, Bravo R. Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J Exp Med. 1997. 186:1757–1762.

23. Kostrikis LG, Huang Y, Moore JP, Wolinsky SM, Zhang L, Guo Y, Deutsch L, Phair J, Neumann AU, Ho DD. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med. 1998. 4:350–353.

24. Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, Goedert JJ, O'Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O'Brien SJ. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science. 1997. 277:959–965.

25. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000. 18:217–242.

26. Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA. 1997. 94:1925–1930.

27. Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996. 4:25–36.

28. Lee CK, Suh JH, Cho YS, Han KH, Chung JB, Chon CY, Moon YM. Chemokine receptor expression of hepatitis B virus-specific CD8+ lymphocyte in chronic B viral infection. Taehan Kan Hakhoe Chi. 2002. 8:363–370.

29. Chang HY, Ahn SH, Kim do Y, Shin JS, Kim YS, Hong SP, Chung HJ, Kim SO, Yoo WD, Han KH. Association between CCR5 promoter polymorphisms and hepatitis B virus infection. Korean J Hepatol. 2005. 11:116–124.