Abstract
IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35–0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99–1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10–1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45–0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development.
Similar content being viewed by others
References
Ferlay J, S. I., Ervik M, Dikshit R, Eser S, Mathers & C, e. a. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC cancer base no. 11 [Internet]. . Lyon, France: International Agency for Research on Cancer 2013.
Yeh FS, Y. M., Mo CC, Luo S, Tong MJ, Henderson BE. Hepatitis B virus, aflatoxins, and hepatocellular carcinoma in southern Guangxi, China. Cancer Res; 1989. 2506–2509.
Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–74.
lecture., C. F. R.-W. a. Viruses, immunity, and cancer: lessons from hepatitis B. . Am J Pathol; 2000. 1117–1132.
Wolf SF, Sieburth D, Sypek J. Interleukin 12: a key modulator of immune function. Stem Cells. 1994;12:154–68.
Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–46.
Becskei A, Grusby M. Contribution of IL-12R mediated feedback loop to Th1 cell differentiation. FEBS Lett. 2007;581(27):5199–206.
Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, et al. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol. 1998;161(7):3400–7.
Brunda MJ, Luistro L, Warrier RR, Wright RB, Hubbard BR, Murphy M, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178:1223–30.
Noguchi Y, Culpepper JA, Richards EC, Old LJ. Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. Proc Natl Acad Sci U S A. 1996;93:11798–801.
Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, et al. Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J Exp Med. 2001;194:1195–205.
Nieters A, Yuan J, Sun CL, Zhang ZQ, Stoehlmacher J, Govindarajan S, et al. Effect of cytokine genotypes on the hepatitis B virus-hepatocellular carcinoma association. Cancer Res. 2005;103(4):740–8.
Ognjanovic S, Yuan J, Chaptman AK, Fan Y, Yu MC. Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA. Carcinogenesis. 2009;30(5):758–62.
Liu L, Xu Y, Liu Z, Chen J, Zhang Y, Zhu J, et al. IL12 polymorphisms, HBV infection and risk of hepatocellular carcinoma in a high-risk Chinese population. Int J Cancer. 2011;128(7):1692–6.
Park JS, Cheong J, Kang JK, Cho JH, Yu S, Shin HD, et al. Association of interleukin-12 gene polymorphism with persistence of hepatitis B virus infection and hepatocellular carcinoma. Korean J Gastroenterol. 2007;50(5):313–8.
Tan A, Gao Y, Yang X, Zhang H, Qin X, Mo L, et al. Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey. Metabolism. 2011;60:1186–92.
Hu L, Xiangjun Z, Liu J, Chu M, Pan S, Jiang J, et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology. 2012;55(5):1426–31.
Shi YY, He L. SHesis. A powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15(2):97–8.
Saxena R, Chawla Y, Verma I, Kaur J. Effect of IL-12B, IL-2, TGF-b1, and IL-4 polymorphism and expression on hepatitis B progression. J Interferon Cytokine Res. 2014;34(2):117–28.
Wang C, Zhang X, Zhu B, Hu D, Wu J, Yu R, et al. Relationships between tumour necrosis factor-α, interleukin-12B and interleukin-10 gene polymorphisms and hepatitis B in Chinese Han haemodialysis patients. Nephrology (Carlton). 2012;17(2):167–74.
Lee KM, Shen M, Chapman RS, Yeager M, Welch R, He X, et al. Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuan Wei, China. Carcinogenesis. 2007;28(7):1437–41.
Chen X, Han S, Wang S, Zhou X, Zhang M, Dong J, et al. Interactions of IL-12A and IL-12B polymorphisms on the risk of cervical cancer in Chinese women. Clin Cancer Res. 2009;15(1):400–5.
Grohmann U, Belladonna M, Bianchi R, Orabona C, Ayroldi E, Fioretti MC, et al. IL-12 acts directly on DC to promote nuclear localization of NF-kappaB and primes DC for IL-12 production. Immunity. 1998;9(3):315–23.
Pikarsky E, Porat R, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431(7007):461–6.
Acknowledgments
This study was supported by the Guangxi Natural Science Foundation (2012GXNSFBA053117), Guangxi Natural Science Fund for Innovation Research Team (2013GXNSFFA019002), Guangxi Collaborative Innovation Center for genomic and personalized medicine (201319), Guangxi Natural Science Fund for Distinguished Young Scholars (2012jjFA40011), and Program for New Century Excellent Talents in University (NCET-12-0653).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary Table 1
SNPs and PCR primer for IL12 allele genotyping. (DOC 30 kb)
Supplementary Table 2
Linkage disequilibrium (LD) information of IL12A variations (DOCX 13 kb)
Rights and permissions
About this article
Cite this article
Tan, A., Gao, Y., Yao, Z. et al. Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population. Tumor Biol. 37, 6343–6348 (2016). https://doi.org/10.1007/s13277-015-4520-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-4520-x