Interactions of IL-12A and IL-12B Polymorphisms on the Risk of Cervical Cancer in Chinese Women

Purpose: Accumulative evidence suggests that interleukin-12 (IL-12) plays a central role in the Th1 responses and thus participates in the carcinogenesis of human papillomavirus–related cervical cancer. We hypothesized that potentially functional polymorphisms in IL12A and IL12B may individually and jointly contribute to cervical cancer risk. Experimental Design: We genotyped IL12A rs568408 [3′ untranslated region (UTR) G>A] and rs2243115 (5′UTR T>G) and IL12B rs3212227 (3′UTR A>C) in a hospital-based study of 404 cervical cancer cases and 404 cancer-free controls. Results: The IL12A rs568408 GA/AA and IL12B rs3212227 AC/CC variant genotypes were associated with a significantly increased risk of cervical cancer [adjusted odds ratio, 1.43; 95% confidence interval (CI), 1.06-1.93; and adjusted odds ratio, 1.30; 95% CI, 0.97-1.75, respectively], compared with their corresponding wild-type homozygotes. Moreover, a significant gene-gene interaction of these 2 loci were evident in the risk of cervical cancer, and subjects carrying variant genotypes of both loci had a 1.82-fold (95% CI, 1.28-2.57) increased risk of cervical cancer. In the stratified analyses, the combined genetic effect was more pronounced in patients who had early-stage tumors or more parities. Subjects carrying rs568408 AG/AA and rs3212227 AC/CC genotypes and having >2 parities showed a 6.00-fold (95% CI, 2.86-12.56) elevated cervical cancer risk (P for multiplicative interaction = 0.046). Conclusion: These findings suggest that IL12A rs568408 and IL12B rs3212227 may individually and jointly contribute to the risk of cervical cancer and may modify cervical cancer risk associated with parity, but these data need further validation.

[1]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[2]  L. Hou,et al.  Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer. , 2007, Carcinogenesis.

[3]  R. Roden,et al.  How will HPV vaccines affect cervical cancer? , 2006, Nature Reviews Cancer.

[4]  C. Wen.  China's plans to curb cervical cancer. , 2005, The Lancet. Oncology.

[5]  L. Luistro,et al.  Antitumor and antimetastatic activity of interleukin 12 against murine tumors , 1993, The Journal of experimental medicine.

[6]  N. Rothman,et al.  Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study. , 2007, Carcinogenesis.

[7]  H. Hausen.  Papillomaviruses and cancer: from basic studies to clinical application , 2002, Nature Reviews Cancer.

[8]  R. Kurman,et al.  Analysis of cytokine profiles in patients with human papillomavirus-associated neoplasms. , 1997, Journal of the National Cancer Institute.

[9]  Theodore R Holford,et al.  Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. , 2006, Blood.

[10]  中平 雅清.  Synergy of IL-12 and IL-18 for IFN-γ Gene Expression : IL-12-Induced STAT4 Contributes to IFN-γ Promoter Activation by Up-Regulating the Binding Activity of IL-18-Induced Activator Protein 1 , 2002 .

[11]  J. Goedert,et al.  Associations of Classic Kaposi Sarcoma with Common Variants in Genes that Modulate Host Immunity , 2006, Cancer Epidemiology Biomarkers & Prevention.

[12]  Jian-Min Yuan,et al.  Effect of cytokine genotypes on the hepatitis B virus‐hepatocellular carcinoma association , 2005, Cancer.

[13]  G. Trinchieri,et al.  Interleukin-12 and the regulation of innate resistance and adaptive immunity , 2003, Nature Reviews Immunology.

[14]  L. Old,et al.  Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  C. Hsieh,et al.  Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. , 1993, Science.

[16]  T. Rohan,et al.  Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. , 2001, JAMA.

[17]  J. Doorbar,et al.  Molecular biology of human papillomavirus infection and cervical cancer. , 2006, Clinical science.

[18]  L Beardsley,et al.  Natural history of cervicovaginal papillomavirus infection in young women. , 1998, The New England journal of medicine.

[19]  G. Trinchieri,et al.  Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells , 1993, The Journal of experimental medicine.

[20]  Piero Musiani,et al.  Combined Allogeneic Tumor Cell Vaccination and Systemic Interleukin 12 Prevents Mammary Carcinogenesis in HER-2/neu Transgenic Mice , 2001, The Journal of experimental medicine.

[21]  E. Guinó,et al.  Polymorphisms within inflammatory genes and colorectal cancer , 2006, Journal of Negative Results in BioMedicine.

[22]  C. Woodman,et al.  Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study , 2001, The Lancet.

[23]  J. Cerhan,et al.  Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival. , 2007, Blood.

[24]  G. Bouma,et al.  A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion , 2002, Genes and Immunity.

[25]  Robert Welch,et al.  Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuan Wei, China. , 2007, Carcinogenesis.

[26]  N. Park,et al.  Interleukin-12 p40 gene (IL12B) polymorphisms and the risk of cervical cancer in Korean women. , 2008, European journal of obstetrics, gynecology, and reproductive biology.

[27]  B. Portmann,et al.  Liver histology and progression of fibrosis in individuals with chronic hepatitis C and persistently normal ALT , 2003, American Journal of Gastroenterology.

[28]  A. Moscicki,et al.  Th 1 Cytokine Patterns in Cervical Human Papillomavirus Infection , 1999 .

[29]  S. Turner,et al.  Cytokine gene single nucleotide polymorphisms and susceptibility to and prognosis in cutaneous malignant melanoma. , 2003, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[30]  A. Moscicki,et al.  Th1 Cytokine Patterns in Cervical Human Papillomavirus Infection , 1999, Clinical Diagnostic Laboratory Immunology.

[31]  M. Rugge,et al.  Interleukin 12 gene polymorphisms enhance gastric cancer risk in H pylori infected individuals , 2005, Journal of Medical Genetics.

[32]  J. She,et al.  IL-12p40 is associated with type 1 diabetes in Caucasian-American families. , 2002, Diabetes.

[33]  C. Meijer,et al.  The presence of persistent high‐risk hpv genotypes in dysplastic cervical lesions is associated with progressive disease: Natural history up to 36 months , 1995, International journal of cancer.

[34]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[35]  G. Trinchieri,et al.  Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes , 1989, Journal of Experimental Medicine.

[36]  G. Saruhan-Direskeneli,et al.  IL-12 and IL-10 polymorphisms and their effects on cytokine production. , 2005, Cytokine.

[37]  G. Trinchieri,et al.  Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells , 1994, The Journal of experimental medicine.

[38]  M. Nakahira,et al.  Synergy of IL-12 and IL-18 for IFN-γ Gene Expression: IL-12-Induced STAT4 Contributes to IFN-γ Promoter Activation by Up-Regulating the Binding Activity of IL-18-Induced Activator Protein 11 , 2002, The Journal of Immunology.

[39]  R. Angeletti,et al.  Regression of cervical intraepithelial neoplasia and loss of human papillomavirus (HPV) infection is associated with cell-mediated immune responses to an HPV type 16 E7 peptide. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[40]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[41]  G. Morahan,et al.  Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele , 2001, Nature Genetics.