肝癌是台灣最常見的癌症之一，估計在2004年死於肝癌有7,108人。許多流行病學研究指出B型肝炎或C型肝炎是發展成肝癌的主要因素。當人體受到病毒感染時，細胞激素對於抵禦病毒的侵襲扮演著很重要的角色。而細胞激素的基因多型性，主要在特定的序列位置上發生突變，與專一性細胞激素的產量有很大的關連性，換言之，細胞激素產生量之多寡決定於細胞激素基因多型性的不同。本篇研究目的為利用病例-對照組的設計，探討細胞激素（IL-10、IFN-γ和TNF-α）的基因型與肝癌之相關性研究。收集個案來自於台南市新樓基督教醫院的123名肝癌病患及相同醫院之120名健檢的健康民眾為對照組。利用病例組和對照組之各種細胞激素的不同基因型分佈做分類比較；區分介白質-10 （-592,-819、-1082和半套體）、干擾素-γ（+874 和 CA repeat）和腫瘤壞死因子-α（-238, -308, -806, -857, -863 and -1031）之不同種基因型特性之間的差異性。根據B型肝炎和C型肝炎病人，區分不同種細胞激素和基因型之差別。結果顯示B型肝炎（OR 37.39, 95％ C.I. 7.28-192.10）和C型肝炎（OR 26.18, 95％ C.I. 4.14-165.53）的發生率與肝癌有顯著相關。肝癌病人與對照組的介白質-10（-592、-819和半套體）、干擾素-γ（+874）和腫瘤壞死因子-α（-238, -308, -806, -857, -863 和-1031）的分佈情形則沒有差異性。結果顯示在B型肝炎或是C型肝炎病人會因為這些細胞激素的基因型態不同而會有效應修飾（effect modification）肝癌之風險性。利用非條件式邏輯回歸法分析，介白質-10-1082（OR 5.78, 95％ C.I. 1.28-26.10）和干擾素-γ 14 CA repeat （OR 0.33, 95％ C.I. 0.13-0.87）與肝癌有顯著之相關。利用條件式邏輯回歸法分析，干擾素-γ 12/12 CA repeat （OR 22.05, 95％ C.I. 2.00-248.24） 的對偶基因頻率與肝癌關係具顯著之差異。結果證實在B型肝炎或是C型肝炎病人的介白質-10（-592、-819和半套體）、干擾素-γ（+874） 和腫瘤壞死因子-α（ -308, -857, -863 和-1031）對於肝癌的發生扮演著修飾因子之角色，干擾素-γ（14 CA repeat）對於肝癌產生的過程可能具有保護作用，此外介白質-10-1082和干擾素-γ（12/12 CA repeat） 可能是具有促進肝癌之作用。

In Taiwan, hepatocellular carcinoma (HCC) is one of the most common types of cancer, than it accounted approximately 7,108 deaths in 2004. Many epidemiological studies have suggested that hepatitis B virus (HBV) and hepatitis C virus (HCV) mainly participate in the development of HCC. Cytokines play an important role in the defense system against viral infection. Cytokine genes are polymorphic at specific sites, and some of these mutations have been associated with different production of the specific cytokines. The aim of this study is to conduct a case-control study to investigate the relationship between cytokine genotypes and the development of HCC. The recruited 123 consecutive HCC patients and 120 controls were from the oncology ward and from at a health check-up program designed, respectively, at Sin-Lau Christian hospital in Tainan. We evaluated differences in the distributions of IL-10 (-592,-819 and -1082) / IFN-γ (+874 and CA repeat) / TNF-α (-238, -308, -806, -857, -863 and -1031) genotypes and other characteristics, as well as HBV and HCV, between HCC patients and controls. The results showed that HBV (OR 37.39, 95% C.I. 7.28-192.10) and HCV (OR 26.18, 95% C.I. 4.14-165.53) were significantly correlated with HCC. There are no differences found in the distribution of IL-10 (-592, -819 and haplotype), IFN-γ (+874) and TNF-α (-238, -308, -806, -857, -863 and -1031) alleles between HCC patients and controls. However, these different alleles can increase the odds ratio of HCC in HBV or HCV patients. Unconditional or conditional logistic regression analysis show allele frequencies of the IL10-1082（OR 5.78, 95％ C.I. 1.28-26.10）, IFN-γ 14 CA repeat （OR 0.33, 95％ C.I. 0.13-0.87） and 12/12 CA repeat（OR 22.05, 95％ C.I. 2.00-248.24） have significant differences.Therefore, the genetic polymorphisms in -592/-819 haplotype of the IL-10 gene, +874 of IFN-γ gene and -308, -857, -863 and -1031 of TNF-α may play a modified role in HCC development in patients with chronic HBV or HCV infection; 14 CA repeat of IFN-γ may be associated with resistance to hepatocellular carcinogenesis; IL10-1082 and 12/12 CA repeat of IFN-γ may induce HCC.

1.Abbas AK, KM Murphy and A Sher. Functional diversity of helper T lymphocytes. Nature 383:787-793, 1996
2.Abraham, LJ and KM Kroeger. Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. Journal of Leukocyte Biology 66(4)：562-566, 1999
3.Abrahamsson J, B Carlsson and L Mellander. Tumor necrosis factor-alpha in malignant disease. Am J Pediatr Hematol Oncol 15: 364-369, 1993
4.Agarwala SS and JM Kirkwood. Interferons in melanoma. Curr Opin Oncol 8:167–174, 1996
5.Alexander Schneidera, Barmadab M Michael, Adam Slivkaa, A John Martina and C David. Whitcomb. Analysis of tumor necrosis factor-α, transforming growth factor-β1, interleukin-10, and interferon-γ polymorphisms in patients with alcoholic chronic pancreatitis. Alcohol 32：19–24, 2004
6.Akiyama K. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res 37: 97-106, 1999
7.Andrew Y, M Shinohara, P-L Wang and Ohura. 15-Deoxy-(12,14)-prostagla
8.Ndin 2 inhibits IL-10 and IL-12 production by macrophages. Biochem. Biophys. Res. Commun. 83: 344-346, 2002
9.Asderakis A, V Pravica, PA Dyer, PJ Sinnott. Hutchinson IX CA-repeat polymorphism in the first intron of the interferon-y (IFN-y) gene. Zmmunofogy 92 (suppl 1): 15.8, 1997
10.Awad MR, V Pravica, A El-Game1, Hasleton P, Sinnott PJ, Hutchinson IV. CA-repeat allele in the first intron of the IFN-y gene is associated with lung allograft fibrosis. Immunology 92 (suppl 1): 13-19, 1997
11.Awata T, C Matsumoto, T Urakami, R Hagura, S Amemiya, Y Kanazawa .Association of polymorphism in the interferon gamma gene with IDDM. Diabetologia 37:1159–1162, 1994
12.Balkwill F, A Mantovani. Inflammation and cancer: back to Virchow? Lancet 357:539–45, 2001
13.Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 61:1942–56, 1988
14.Beasley RP, LY Hwang, CC Lin et al. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet ii：1129–33, 1981
15.Belardelli F. Role of interferons and other cytokines in the regulation of the immune response. APMIS 103: 161–179, 1995
16.Ben-Ari Z, E Mor, O Papo et al. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol 98：144-150, 2003
17.Bertoletti A, MM D’Elios, C Boni et al. Different cytokine profiles of intrahepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology.112:193–199, 1997
18.Beutler BA, The role of tumor necrosis factor in health and disease. Journal of Rheumatology 26(Suppl 57)：16-21, 1999
19.Beutler B. TNF in pathophysiology: biosynthetic regulation. Journal of Investigative Dermatology 95(6 Suppl)： 81S-84S, 1990
20.Beutler B, IW Milsark and AC Cerami. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229(4716)：869-871, 1985
21.Borm PJ et al., Spontaneous and stimulated release of tumor necrosis factor-alpha (TNF) from blood monocytes of miners with coal workers' pneumoconiosis. American Review of Respiratory Disease.138(6)：1589-1594, 1988
22.Brodie SJ, VG Sasseville, KA Reimann, MA Simon, PK Sehgal and DJ Ringler. Macrophage function in simian AIDS. Killing defects in vivo are independent of macrophage infection, associated with alterations in Th phenotype, and reversible with IFN-gamma. J Immunol 153 :5790–5801, 1994
23.Boehm U, T Klamp, M Groot and JC Howard. Cellular Responses to interferon-γ. Annu Rev Immunol.15：749-795, 1997
24.Cancer Registry Annual Report Republic of China, 1995
25.Cabrera M et al., Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. Journal of Experimental Medicine 182(5)：1259-1264, 1995
26.Cathering J Edwards-Smith, R Jonsson Julie, M Purdie David. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 30(2)：526-530, 1999
27.Chau Gar-Yang, Wu Chew-Wun and Chang Tai-Jay et al. Serum interleukin-10 but not interleukin-6 Is related to clinical outcome in patients with resectable hepatocellular carcinoma. Annals of Surgery 231(4)：552-558, 2000
28.Chen C-J, M-W Yu, Y-F Liaw. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroen Hepatol 12: S294–S308, 1997
29.Chen C-J, K-Y Liang, Chang A-S et al. Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma. Hepatology 13: 398–406, 1991
30.Chisari F V and C Ferrari. Hepatitis B virus immunopathogenesis. Annu. Rev. Immunol. 13:29, 1998
31.Chouchane L et al., Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors. Cancer 80(8)：1489-1496, 1997
32.Clerici M, TA Wynn, JA Berzofsky, SP Blatt, CW Hendrix, A Sher, RL Coffman et al. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest 93:768-775, 1994
33.Clerici M, C Balotta, A Salvaggio, C Riva, D Trabattoni, L Papagno, A Berlusconi et al. Human immunodeficiency virus (HIV) phenotype and interleukin-2/interleukin-10 ratio are associated markers of protection and progression in HIV infection. Blood 88:574-579, 1996
34.Coleman William B. Mechanisms of Human Hepatocarcinogenesis. Current Molecular Medicine 3 :573-588, 2003
35.Colombo M. Hepatitis C virus and hepatocellular carcinoma. Baillieres Best Pract Res Clin Gastroenterol 13:519–28, 1999
36.Costeas PA, L Koumas, A Koumouli, A Kyriakou-Giantsiou, A Papaloizou. Cytokine polymorphism frequencies in the Greek Cypriot population. Eur J Immunogenet 30: 341–343, 2003
37.Coussens LM and Z Werb. Inflammation and cancer. Nature 420: 860–867, 2002
38.Cox ED, SC Hoffmann, BS DiMercurio et al. Cytokine polymorphism analyses indicate ethnic differences in the allelic distribution of interleukine-2 and interleukine-6. Transplantation 72: 720–726, 2001
39.De Francesco MA, A Caruso and F Dima, Cantalamessa A, Canaris AD, Folghera S, Fiorentini S, Flamminio G, Licenziati S, Peroni L, Gao J, Garotta G, Turano A. IFN-gamma restores HIV- and non-HIV-specific cell mediated immune response in vitro and its activity is neutralized by antibodies from patients with AIDS. Scand J Immunol 43:94–100, 1996
40.Department of Health, the Executive Yuan, Taiwan, ROC. 2006.
41.Di Bisceglie AM. Malignant tumors of the liver. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s diseases of the liver, 8th ed. Philadelphia: Lippincott- Raven Publishers, 1281–1304, 1999
42.Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 26:34S–8S, 1997
43.Di Bisceglie AM, Goodman ZD, Ishak KG, et al. Long-term clinical and histopathological follow-up of posttransfusion hepatitis. Hepatology 14:969–74, 1991
44.Donato F, P Boffetta and M Puoti. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 75:347–54, 1998
45.Dorman SE, SM Holland. Interferon-gamma and interleukin- 12 pathway defects and human disease. Cytokine Growth Factor Rev 11:321-333, 2000
46.Eskdale J, G Gallagher. A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics 42:444–449,1995
47.Eskdale J, D Kube and G Gallagher. A second polymorphic dinucleotide repeat in the 50 flanking region of the human IL-10 gene. Immunogenetics 45:82–83, 1996
48.Eskdale J, J McNicholl, P Wordsworth et al. Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility. Lancet 352:1282–1283, 1998
49.Eskdale J, P Wordsworth, S Bowman et al. Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus. Tissue Antigens 49:635–639, 1997
50.Esther Crawley, Richard Kay, James Sillibourne, Pritash Patel, Ian Hutchinson, Patricia Woo. Polymorphic haplotypes of the interleukin-10 5’ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Artheritis and Rheumatism 42(6)：1101-1108, 1999
51.Farci P, HJ Alter, S Govindarajan, DC Wong and R Engle and RR Lesniewski. Lack of protective immunity aginst reinfection with hepatitis C virus. Science. 258：135-140, 1992
52.Ferrari C, A Valli, L Galati, A Penna, P Scaccaglia, T Giuberti and C Schianchi et al. T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections. Hepatology 19:286-295, 1994
53.Gray PW and Goeddel DV. Human immune interferon (IFN-gamma) gene sequence and structure. Basic Life Sci 25:35– 61, 1983
54.Guidotti LG and Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19:65-91, 2001
55.Hashem B. El-Serag, M.D., M.P.H. Hepatocelluar carcinoma- An epidemiologic view. Journal of Clinical Gastroenterology 35(suppl. 2)：S72-S78, 2002
56.Heagy W, Groopman J, Schindler J and Finberg R. Use of IFN-gamma in patients with AIDS. J Acquir Immune Defic Syndr 3:584–590, 1990
57.Higuchi T, Seki N, Kamizono S et al. Polymorphism of the 50-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens 51: 605–612, 1998
58.Ho Sheng-Yow, Wang Ying-Jan, Chen Hen-Li, Chen Chih-Hung, Chang Chih-Jen, Wang Po-Jen, Chen Helen H.W. & Guo How-Ran, Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the )308 tumor necrosis factor-a promoter gene. Cancer Causes and Control 15：657-663, 2004
59.Howard M, O’Garra A. Biological properties of interleukin 10. Immunol. Today 13: 198-200, 1992
60.Huang, S.L., C.H. Su, and S.C. Chang, Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. American Journal of Respiratory & Critical Care Medicine 156(5)：1436-1439, 1997
61.Hung-Cheng Lai, Cheng- Chang Chang et al. Genetic polymorphism of the interferon-γgene in cervical carcinogenesis. Int. J. Cancer 113：712-718, 2005
62.Hyoung Doo Shin, Byung Lae Park, Lyoung Hyo Kim et al. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. Human Molecular Genetics 12：901-906, 2003
63.Ikeda K, Saitoh S, Koida I, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18:47–53, 1993
64.lkner DM, Grant SCD, Yonan N et al. Qtokine genotypes and heart transplant rejection. Tmnspkzntation 64: 776-778, 1997
65.Jaattela, M., Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachectin. Laboratory Investigation.64(6)：724-742, 1991
66.J.A. Trejaut, Z.-U. Tsai, H.-L. Lee, Z.-X. Chen, M. Lin. Cytokine gene polymorphisms in Taiwan. Tissue Antigens 64：492-499, 2004
67.Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E., and Thun, M.J. C.A. Cancer J. Clin., 53： 5-26, 2003
68.JF. Lin ZY. Hsieh MY. Tsai JF. Wang LY. Changing prevalence of hepatitis C virus genotypes： molecular epidemiology and clinical implications in the hepatitis C virus hyperendemic areas and a tertiary referral center in Taiwan. Journal of Medical Virology. 65（1）：58-65, 2001
69.John S, Myerscough A, Marlow A, Hajeer A, Silman A, Ollier W, Worthington J. Linkage of cytokine genes to rheumatoid arthritis. Evidence of genetic heterogeneity. Ann Rheum Dis 57 :361–365, 1998
70.Jose M. Ladero, Miguel Fernandez-Arquero et al. Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease. Liver 22：245-251, 2002
71.Kakumu S, A Okumura, T Ishikawa et al. Serum levels of IL-10, IL-15 and soluble tumor necrosis factor-alpha (TNF-a) receptors in type C chronic liver disease. Clin Exp Immunol 109:458–463, 1997
72.Kato S, M Onda, S Yamada, N Matsuda, A Tokunaga and N Matsukura. Association of the interleukin-1 beta genetic polymorphism and gastric cancer risk in Japanese. J Gastroenterol 36: 696–699, 2001
73.Katsikis PD, CQ Chu and FM Brennan et al. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 179: 1517–1527, 1994
74.Kawaguchi Y, A Tochimoto, N Ichikawa et al. Association of IL1A gene polymorphisms with susceptibility to and severity of systemic sclerosis in the Japanese population. Arthritis Rheum 48: 186–92, 2003
75.Khatri VP, TA Fehniger, RA Baiocchi, F Yu, MH Shah, DS Schiller, M Gould, G RT azzinelli, ZP Bernstein and MA Caligiuri. Ultra low dose interleukin-2 therapy promotes a type 1 cytokine profile in vivo in patients with AIDS and AIDS-associated malignancies. J Clin Invest 101:1373–1378, 1998
76.Kuo G, Choo Q-L, Alter HJ et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 244：362-364, 1989
77.Kiyosawa K, Sodeyama T, Tanaka E et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma：Analysis by detection of antibody to hepatitis C virus. Hepatology 12：671-675, 1990
78.Kiyosawa K, Tanaka E, Sodeyama. Hepatitis C virus and hepatocellular carcinoma. In: Reesnick HW, ed. Hepatitis C virus, vol. 62. Current studies in hematology and blood transfusion. Basel: Karger :161–180, 1998
79.Kiyoshi Migita, Seiji Miyazoe, Yumi Maeda, Manabu Daikoku, Seigo Abiru,
80.Tshihito Ueki, Koji Yano, Shinya Nagaoka, Takehiro Matsumoto, Kazuhiko Nakao, Keisuke Hamasaki, Hiroshi Yatsuhashi, Hiromi Ishibashi and Katsumi Eguchi. Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection—association between TGF-b1 polymorphisms and hepatocellular carcinoma. Journal of Hepatology 42：505–510, 2005
81.Kroeger KM, KS Carville, and LJ Abraham. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Molecular Immunology 34(5)：391-399, 1997
82.Kroeger, KM and LJ Abraham, Identification of an AP-2 element in the -323 to -285 region of the TNF-alpha gene. Biochemistry & Molecular Biology International 40(1)：43-51, 1996
83.Lai CL, Gregory PB, Wu PC, Lok AS, Wong KP and Ng MM. Cancer 60： 1107-1110, 1987
84.Landis SH, Murray T, Bolden S, and Wingo PA. C.A. Cancer J. Clin.49：8-31, 1999
85.Landolfo S, G Gribaudo, A Angeretti and M Gariglio. Mechanisms of viral inhibition by interferons. Pharmacol Ther 65:415–442, 1995
86.Lasarte JJ, M Garcia-Granero, A Lopez, N Casares, N Garcia, MP Civeira and F Borras-Cuesta et al. Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C. Hepatology 28:815-822, 1998
87.Letizia Scola , Antonio Crivello , Vincenzo Marino , Vito Gioia , Alberto Serauto and Domenico Lio. IL-10 and TNF-a polymorphisms in a sample of Sicilian patients affected by tuberculosis: implication for ageing and life span expectancy. Mechanisms of Ageing and Development 124：569-572, 2003
88.Lio D, L Scola, A Crivello, G Colonna-Romano, G Candore, M Bonafe`, L Cavallone, C Franceschi and C Caruso. Gender specific association between -1082 IL-10 promoter polymorphism and longevity. Gene Immun. 3：30-33, 2002a
89.Lio D, L Scola, A Crivello, M Bonafe`, C Franceschi, F Olivieri, G Colonna-Romano, G Candore and C Caruso. Allele frequencies of -874T to/A single nucleotide polymorphism at the first intron of interferon-g gene in a group of Italian centenarians. Exper. Gerontol. 37：317-321, 2002b
90.Lio D, V Marino, A Serauto, V Gioia et al. Genotype frequencies of the +874T to A single nucleotide polymorphism in the first intron the interferon-γgene in a sample of Sicilian patients affected by tuberculosis. European Journal of Immunogenetics 29：371-374, 2002c
91.Llorente L, Y Richaud-Patin and R Fior et al. In vivo production of interleukin 10 by non-T cells in rheumatoid arthritis, Sjo¨gren’s syndrome, and systemic lupus erythematosus: a potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 37: 1647–1655, 1994
92.Louie L. Cytokine polymorphism Workshop Component Anthropology of cytokine gene variation. In: JA Hsmsen, B Dupont, eds. HLA 2002, Immunobiology of the Human MHC. Proceedings of the 13th International Histocompatibility Workshop and Conferences, Vol. 2. IHWG: Victoria BC Canada and Seattle, WA, USA, 2002.
93.Lone Skov, H Michael and Bo Bang Allen et al. Basal cell carcinoma is associsted with high TNF-α release but not with TNF-α polymorphism at position -308. Experimental Dermatology 12：772-776, 2003
94.Wallin KL, F Wiklund, T Angstrom, F Bergman, U Stendahl, G Wadell, G Hallmans and J Dillner. Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. Engl J Med 341:1633– 1638, 1999
95.Mathers CD, K Shibuya, C Boschi-Pinto, AD Lopez and Murray, CJ BMC Cancer 2： 36, 2002
96.Marshall SE, AJ McLaren and EF McKinney et al. Donor cytokine genotype influences the development of acute rejection after renal transplantation. Transplantation 71: 469–476, 2001
97.McNicholl JM, MV Downer, V Udhayakumar, CA Alper, DL Swerdlow Host-pathogen interactions in emerging and re-emerging infectious diseases: a genomic perspective of tuberculosis, malaria, human immunodeficiency virus infection, hepatitis B, and cholera. Annu. Rev. Public Health 21：15-/46, 2000
98.Meenagh A, F Williams and OA Ross et al. Frequency of cytokine polymorphisms in populations from western Europe, Africa, Asia, the Middle East and South America. Hum Immunol 63: 1055–1061, 2002
99.Messer G et al. Allelic variation in the TNF-beta gene does not explain the low TNF-beta response in patients with primary biliary cirrhosis. Scandinavian Journal of Immunology 34(6)：735-740, 1991
100.Merja Helminen, Nina Lahdenpohja and Mikko Hurme. Polymorphism of the Interleukin-10 gene is associated with susceptibility to Epstein-Barr Virus infection. The Journal of Infectious Diseases 180：496-499, 1999
101.Merja E Helminen, Sanna Kilpinen, Miia Virta and Mikko Hurme. Susceptibility to primary Epstein-Barr virus infection is associated with interleukin-10 gene promoter polymorphism. The Journal of Infectious Diseases 184:777–780, 2001
102.Migita K et al. Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection—association between TGF-b1 polymorphisms and hepatocellular carcinoma. Journal of Hepatology 42：505–510, 2005
103.Mok CC, JS Lanchbury, DW Chan and CS Lau. Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum 41: 1090–1095, 1998
104.Moore KW, DS Riminton, RDW Malefyt, V P ieira and TR Mosmann. Interleukin 10. Annu. Rev. Immunol. 11: 165-190, 1993
105.Moore RJ, et al., Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nature Medicine 5(7)：828-831, 1999
106.Mosmann TR and RL Coffman. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145-173, 1989
107.Muller U, U Steinhoff, R LF eis, S Hemmi, J Pavlovic, RM Zinkernagel and M Aguet. Functional role of type I and type II interferons in antiviral defense. Science 264: 1918–1921, 1994
108.Munro LR, PW Johnston, NA Marshall, SJ Canning, SG Hewitt, K Tveita and MA Vickers. Polymorphisms in the interleukin-10 and Interferon gamma genes in Hodgkin Lymphoma. Leukemia & Lymphoma 44 (12)：2083–2088, 2003
109.Nakamoto Y, LG Guidotti, CV Kuhlen, P Fowler, and FV Chisari. Immune pathogenesis of hepatocellular carcinoma. J. Exp. Med. 188:341, 1998
110.Nakamura T, RK Lee, SY Nam, ER Podack, K Bottomly and RA Flavell. Roles of IL-4 and IFN-gamma in stabilizing the T helper cell type 1 and 2 phenotype. J Immunol 158:2648 –2653, 1997
111.Neumann DA, JR Lane, GS Allen, A Herskowitz and Rose NR. Viral myocarditis leading to cardiomyopathy: do cytokines contribute to pathogenesis?. Clin. Immunol. 68:181-190, 1993
112.Noguchi E, M Shibasaki, T Arinami et al. Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy 28: 449–453, 1998
113.Nieters Alexandra, Jian-Min Yuan et al. Effect of Cytokine Genotypes on the Hepatitis B Virus-Hepatocellular Carcinoma Association. Cancer 103：740-748, 2005
114.Opdal Siri H, Opstad Anette, Vege Åshild, and O Torleiv. Rognum. IL-10 gene polymorphisms are associated with infectious cause of sudden infant death. Human Immunology 64：1183–1189, 2003
115.Oriss TB, SA McCarthy, BF Morel, MA Campana and PA Morel. Crossregulation between T helper cell (Th)1 and Th2: inhibition of Th2 proliferation by IFN-gamma involves interference with IL-1. J Immunol 158:3666 –3672, 1997
116.Park KS, MY Kim and JW Mok. NcoI restriction fragment length polymorphism at -308 of the tumor necrosis factor alpha (TNFA) promoter region in Korean. Jpn J Hum Genet 42: 241–247, 1997
117.Parkin, D.M., Pisani, P., and Ferlay, J. C.A. Cancer J. Clin., 49：33-64, 1999
118.Partanen R, H Koskinen, and K Hemminki, Tumour necrosis factor-alpha (TNF-alpha) in patients who have asbestosis and develop cancer. Occupational & Environmental Medicine 52(5)：316-319, 1995
119.Payvandi F, S Amrute and P Fitzgerald-Bocarsly. Exogenous and endogenous IL-10 regulate IFN-alpha production by peripheral blood mononuclear cells in response to viral stimulation. J Immunol 160:5861-5868, 1998
120.Penna A, G Del Prete, A Cavalli et al. Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. Hepatology 25:1022–1027, 1997
121.Perrey C, V Pravica, PJ Sinnott and Hutchinson. Genotyping for polymorphisms in interferon-gamma, interleukin-10, transforming growth factor-beta 1 and tumour necrosis factor-alpha genes: a technical report. Transpl Immunol 6:193–197, 1998
122.Pociot F et al. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. European Journal of Immunology 23(1)：224-231, 1993
123.Pociot F, R Veijola, J Johannesen, PM Hansen, T Lorenzen, AE Karlsen, H Reijonen, M Knip and J Nerup. Analysis of an interferon-gamma gene (IFNG) polymorphism in Danish and Finnish insulin-dependent diabetes mellitus (IDDM) patients and control subjects. Danish Study Group of Diabetes in Childhood. J Interferon Cytokine Res 17 :87–93, 1997
124.Pohl C, A Hombach and W Kruis. Chronic inflammatory bowel disease and cancer. Hepatogastroenterology 47:57–70, 2000
125.Porat O.The effect of tumor necrosis factor alpha on the activity of lipoprotein lipase in adipose tissue. Lymphokine Research 8(4)：459-469, 1989
126.Poynard T, P Bedossa, P Opolon et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 349:825–32, 1997
127.Pravica V, A Asderakis, C Perrey, A Hajeer, PJ Sinnott and IV Hutchinson. In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene. Eur J Immunogenet 26:1–3, 1999
128.Pravica V, C Perrey, A Stevens, JH Lee and IV Hutchinson. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61: 863–866, 2000
129.Raymond T. Cytokine polymorphisms and hepatocellular carcinoma-to B or not to B. Cancer 103（4）：654-656, 2005
130.Rehermann B. Immune responses in hepatitis B virus infection. Semin Liver Dis 23：21-38, 2003
131.Reynard MP, D Turner and CV Navarrete. Allele frequencies of polymorphisms of the tumour necrosis factor-alpha, interleukin-10, interferon-gamma and interleukin-2 genes in a North European Caucasoid group from the UK. Eur J Immunogenet 27: 241–249, 2000
132.Rossouw Manda, J Nel Hendrik, S Cooke Graham, D van Helden Paul, G Hoal Eileen. Association between tuberculosis and a polymorphic NFκB binding site in the interferon γ gene. The Lancet 361：1871-1872, 2003
133.Ruiz-Linares A. Dinucleotide repeat polymorphism in the interferon-gamma (IFNG) gene. Hum Mol Genet 2: 1508, 1993
134.Sankaran D, S Ashraf, A Asderakis et al. Recipient tumour necrosis factor-a and interleukin-10 gene polymorphisms predict acute graft rejection following renal transplantation. Tmns Zmmunol (submitted).
135.Shacter E and SA Weitzman. Chronic inflammation and cancer. Oncology 16:217–229, 2002
136.Siegmund T, KH Usadel, H Donner, J Braun, PG Walfish, K Badenhoop. Interferon-gamma gene microsatellite polymorphisms in patients with Graves’ disease. Thyroid 8:1013–1017, 1998
137.Simonetti RG, C Camma , F Fiorello, F Politi, G D'Amico, and L Pagliaro. Dig. Dis. Sci. 36：962-972, 1991
138.Song Le H, Vu Q Binh, Dinh N Duy, Jurgen FJ Kun et al. Serum cytokine profiles associated with clinical presentation in Vietnamese infected with hepatitis B virus. Journal of Clinical Virology 28：93-103, 2003
139.Suganuma M et al. Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice. Cancer Research 59(18)：4516-4518, 1999
140.Sullivan KE et al. A promoter polymorphism of tumor necrosis factor alpha associated with systemic lupus erythematosus in African-Americans. Arthritis & Rheumatism 40(12)： 2207-2211, 1997
141.Sun CA, Chen HC, Lu SN, Chen CJ, Lu CF, You SL and Lin SH. Persistent hyperendemicity of hepatitis C virus infection in Taiwan：the important role of iatrogenic risk factors. Journal of Medical Virology. 65（1）：30-34, 2001
142.Stevens RG, EJ Merkle and ED Lustbader. Int. J. Cancer, 33： 453-458, 1984
143.Tartour E, A Gey, X Sastre-Garau, L Surin, I ombard, V Mosseri, WH Fridman. Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. J Natl Cancer Inst 90:287–294, 1998
144.Turner DM, DM Williams, D Sankaran et al. An investigation of polymorphism in the interleukin 10 gene promoter. Eur J Immunogenet 24:1–8, 1997
145.Turner DM, D Sankaran, SCD Grant et al. The effect of polymorphism in the TNF-α and IL-10 genes on heart transplant rejection. Int J Heart Lung Tmnsplunt 16: 108, 1997
146.Turner DM, DM Williams, D Sankaran, M Lazarus, PJ Sinnott and IV Hutchinson. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8, 1997
147.Uboldi de Capei MU, E Dametto, ME Fasano, S Rendine and ES Curtoni. Genotyping for cytokine polymorphisms: allele frequencies in the Italian population. Eur J Immunogenet 30: 5–10, 2003
148.Ullum H, LA Cozzi, K Bendtzen, V J ictor, PC Gotzsche, AN Phillips, P Skinhoj and PB Klarlund. Low production of interferon gamma is related to disease progression in HIV infection: evidence from a cohort of 347 HIV-infected individuals. AIDS Res Hum Retroviruses 13:1039–1046, 1997
149.Vandenbroeck K, G Opdenakker, A Goris, R Murru, A Billiau and MG Marrosu. Interferon-gamma gene polymorphismassociated risk for multiple sclerosis in Sardinia. Ann Neurol 44:841–842, 1998
150.Wasley A and MJ Alter. Epidemiology of hepatitis C：geographic differences and temporal trends. Seminar in Liver Disease 20（1）：1-16, 2000
151.Werner Koch, Klaus Tiroch, Nicolas von Beckerath, Albert Scho mig, Adnan Kastrati. Tumor necrosis factor-a, lymphotoxin-γ, and interleukin-10 gene polymorphisms and restenosis after coronary artery stenting. Cytokine 24：161-171, 2003
152.Wilson AG et al., Effects of a tumor necrosis factor (TNF-alpha) promotor base transition on transcriptional activity. British Journal of Rheumatology 33：89-97, 1994
153.Wu Ming-Shiang, Wu Chun-Ying et al. Interleikin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int. J. Cancer 104：617-623, 2003
154.www.XINHUANET.com
155.Yoshida H, Y Shiratori, M Moriyama et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med 131: 174–181, 1999
156.Yu ML, Chuang WL, Chen SC, Dai CY, Hou C, Wang JH, Lu SN, Huang Ziv Ben-Ari, Eytan Mor et al. Cytokine gene polymorphisms in patients infected with Hepatitis B Virus. The American Journal of Gastroenterology 98：144-150, 2003