肿瘤坏死因子α-308位点基因多态与环境因素对广东省顺德区肝癌的影响研究
|
摘要
在2006年全国第三次死因回顾性抽样调查中发现,癌症是广东省顺德区居民的首位死因,而肝癌死亡率居癌症死因顺位的第一位。2004-2005年顺德肝癌死亡率49.84/10万,超过全国死亡水平。肝癌潜在减寿年数(PYLL)占恶性肿瘤38.60%,该区居民去除肝癌后寿命可延长1.21岁,肝癌正严重威胁着该区居民的生命。目前有关顺德区肝癌的流行病学研究较少,人们对肝癌高发的主要危险因素尚不清楚,因此对顺德区肝癌进行流行病学调查,探索危险因素有重要意义。
研究目的:
通过1:1匹配的病例对照研究,探讨顺德区肝癌的危险因素;研究肿瘤坏死因子(TNF)α-308位点基因多态与肝癌遗传易感性的关系,以及TNF-α-308位点基因多态与环境因素在肝癌发生中的交互作用;分析肝癌患者的出生顺序初步了解环境因素与遗传因素在该区肝癌发生中的相对作用。
对象与方法:
研究对象来源于顺德区医院2004-2007年住院的并在该区居住10年及以上,顺德籍肝癌新发病例及同胞。对照按照1:1匹配的方法收集,要求其未患肝癌,在该区居住10年及以上、与病人同村、同性别、年龄与病例诊断年龄±3岁,无血缘关系。
相关测量包括:(1)问卷调查:调查对象的一般人口学特征、吸烟史、饮酒史、食物摄入情况、饮水状况、相关疾病史,出生顺序等。(2)实验室检测:○1用酶联免疫吸附试验(ELISA)检测HBV感染五项指标、甲胎蛋白、丙肝抗体、肝吸虫抗体。○2用聚合酶链反应-限制片段长度多态性方法(PCR-RELP)分析TNF-α-308位点。
先应用条件Logistic回归模型分析吸烟、饮酒、TNF-α-308基因多态等因素与肝癌的关系和它们之间的交互作用,然后对肝癌患者的出生顺序进行初步分析。
结果:
共调查病例对照81对,病例同胞共计368人(含病例),其中有肝癌患者89人。采集病例对照血样78对,其中男性70对,女性8对。
(1)应用1:1匹配的病例对照研究方法,发现TNF2等位基因在病例组和对照组的分布差异有统计学意义(P=0.012),OR值为2.67(95%CI:1.24一5.74)。
(2)应用条件Logistic回归模型分析顺德区肝癌的危险因素,发现HBsAg、肝病史、饮酒量是肝癌发生的主要危险因素。
(3)HBsAg与TNF2等位基因存在交互作用:其OR值为19.83(95%CI:4.20-93.61);超相对危险比(RERI)为2.22,交互作用归因比(API)为0.29,两因素交互作用指数(SI)为1.50。
(4)肝病史与TNF2等位基因存在交互作用:其OR值为7.63(95%CI:1.05-67.71);其RERI为2.22,API为0.29,SI为1.50。
(5)饮酒与TNF2等位基因存在交互作用:其OR值为4.57(95%CI:1.62-12.88);其RERI为1.39,API为0.30,SI为1.63。
(6)HBsAg(+)组肝癌发生与出生顺序有关;而HBsAg(-)组肝癌发生与出生顺序无关。
结论:
(1)TNF-α-308基因多态与肝癌有关联,TNF2等位基因可能是肝癌的遗传易感基因。
(2)应用1:1匹配的病例对照研究方法探讨顺德区居民肝癌危险因素,发现HBsAg、饮酒量、肝病史是肝癌发生的主要环境危险因素。
(3)HBsAg、饮酒、肝病史与TNF2等位基因存在交互作用。
(4)肝癌患者出生顺序分析提示HBV感染是顺德区肝癌发生的重要环境因素,控制HBV感染后,遗传因素对该区肝癌发生的作用不容忽视。
It was reported that cancer was in the first place of the death causes in Shunde, Guangdong and primary liver cancer (PLC) mortality was the first in Cancer from the Third Time of Nationwide Death Cause Sample Survey in 2006.PLC mortality was 49.84/1,000,000 above national average in Shunde in 2005.PYLL of PLC occupied cancer 38.60%.removed PLC,the resident can live 1.21 years longer.The people was severity threaten by PLC. But the studies on epidemiology of Primary Live Cancer in Shunde were seldom reported. The risk factors of PLC were not identify .So, it was necessary explore risk factors of PLC in Shunde City and this work had a certain realistic significance.
Purposes:
To performed a case-control study to explore risk factors of PLC, to research the association between genetic polymorphisms of the human tumor necrosis factor-α-308 position and susceptibility to PLC, and to probe the interaction between environmental and genetic factors in hepatocarcinogenesis by applying molecular biological technology .
To analyse the birth orders of PLC cases, trying to know the relative roles of environmental and genetic factors in Hepatocarcinogenesis.
Objects and methods:
Subjects were PLC patient in hospital from 2004 to 2007 and sibling who lived in Shunde above 10 years. The controls who didn't have PLC, not blood relation with patient at the same village, same sex, age±3 years, living in Shunde above 10 years.
The contents of survey include:(1) Questionnaire: general conditions;personal history of smoking, drinking,eating, drink water,disease status, birth order, etc;(2)Laboratory examination:○1 to detect HBV, HCV,AFP, liver fluke by ELISA .○2 to analyze TNF-α-308 position by PCR-RELP.
We first applied conditional logistic regression analysis to explore the main effects and interactional effects of HBV, smoking, drinking,TNF2in hepatocarcinogenesis. Then we analyzed the birth orders of PLC cases.
Results:
(1) The frequencies of allele TNF2 were significant differences between case group and control group (P=0.012), with the OR of 2.67 (95%CI: 1.24-5.74).
(2) Applied conditional logistic regression to explore risk factors of PLC , Hepatitis B, alcohol consumption, liver desease history were associated with increased risks of PLC in this study.
(3) HBsAg was interacted with the TNF2 allele during the generation of PLC, With the OR=19.83(95%CI:4.20-93.61); their RERI were 14.39, their API were 0.7253,their SI were 4.23.
(4) Liver desease history was interacted with the TNF2 allele during the generation of PLC, With the OR=7.63(95 %CI:1.05-67.71),their RERI were 2.22, their API were 0.29,their SI were 1.50.
(5) Alcohol consumption was interacted with the TNF2 allele during the generation of PLC, With the OR=4.57(95 %CI:1.62-12.88),their RERI were 1.39, their API were 0.30,their SI were 1.63.
(6) No relation was found between birth order and pathogenesis of PLC in the patient of HBsAg (-),but in the patient of HBsAg(+) birth order had relation with pathogenesis of PLC.
Conclusion:
(1) There was association between genetic polymorphisms of the human tumor necrosis factor-α-308 position and PLC; the TNF2 allele was susceptibility to PLC.
(2) Applied conditional logistic regression to explore risk factors of PLC , Hepatitis B, alcohol consumption, liver desease history were associated with increased risks of PLC in this study.
(3) The TNF2 allele was interacted with HBsAg, liver desease history, alc-ohol consumption.
(4) Hepatitis B played more important role than genetic factors in hepatica-rcinogenes in Shunde.But control Hepatitis B, genetic factors would play important role in hepatocarcinogenesis .
研究目的:
通过1:1匹配的病例对照研究,探讨顺德区肝癌的危险因素;研究肿瘤坏死因子(TNF)α-308位点基因多态与肝癌遗传易感性的关系,以及TNF-α-308位点基因多态与环境因素在肝癌发生中的交互作用;分析肝癌患者的出生顺序初步了解环境因素与遗传因素在该区肝癌发生中的相对作用。
对象与方法:
研究对象来源于顺德区医院2004-2007年住院的并在该区居住10年及以上,顺德籍肝癌新发病例及同胞。对照按照1:1匹配的方法收集,要求其未患肝癌,在该区居住10年及以上、与病人同村、同性别、年龄与病例诊断年龄±3岁,无血缘关系。
相关测量包括:(1)问卷调查:调查对象的一般人口学特征、吸烟史、饮酒史、食物摄入情况、饮水状况、相关疾病史,出生顺序等。(2)实验室检测:○1用酶联免疫吸附试验(ELISA)检测HBV感染五项指标、甲胎蛋白、丙肝抗体、肝吸虫抗体。○2用聚合酶链反应-限制片段长度多态性方法(PCR-RELP)分析TNF-α-308位点。
先应用条件Logistic回归模型分析吸烟、饮酒、TNF-α-308基因多态等因素与肝癌的关系和它们之间的交互作用,然后对肝癌患者的出生顺序进行初步分析。
结果:
共调查病例对照81对,病例同胞共计368人(含病例),其中有肝癌患者89人。采集病例对照血样78对,其中男性70对,女性8对。
(1)应用1:1匹配的病例对照研究方法,发现TNF2等位基因在病例组和对照组的分布差异有统计学意义(P=0.012),OR值为2.67(95%CI:1.24一5.74)。
(2)应用条件Logistic回归模型分析顺德区肝癌的危险因素,发现HBsAg、肝病史、饮酒量是肝癌发生的主要危险因素。
(3)HBsAg与TNF2等位基因存在交互作用:其OR值为19.83(95%CI:4.20-93.61);超相对危险比(RERI)为2.22,交互作用归因比(API)为0.29,两因素交互作用指数(SI)为1.50。
(4)肝病史与TNF2等位基因存在交互作用:其OR值为7.63(95%CI:1.05-67.71);其RERI为2.22,API为0.29,SI为1.50。
(5)饮酒与TNF2等位基因存在交互作用:其OR值为4.57(95%CI:1.62-12.88);其RERI为1.39,API为0.30,SI为1.63。
(6)HBsAg(+)组肝癌发生与出生顺序有关;而HBsAg(-)组肝癌发生与出生顺序无关。
结论:
(1)TNF-α-308基因多态与肝癌有关联,TNF2等位基因可能是肝癌的遗传易感基因。
(2)应用1:1匹配的病例对照研究方法探讨顺德区居民肝癌危险因素,发现HBsAg、饮酒量、肝病史是肝癌发生的主要环境危险因素。
(3)HBsAg、饮酒、肝病史与TNF2等位基因存在交互作用。
(4)肝癌患者出生顺序分析提示HBV感染是顺德区肝癌发生的重要环境因素,控制HBV感染后,遗传因素对该区肝癌发生的作用不容忽视。
It was reported that cancer was in the first place of the death causes in Shunde, Guangdong and primary liver cancer (PLC) mortality was the first in Cancer from the Third Time of Nationwide Death Cause Sample Survey in 2006.PLC mortality was 49.84/1,000,000 above national average in Shunde in 2005.PYLL of PLC occupied cancer 38.60%.removed PLC,the resident can live 1.21 years longer.The people was severity threaten by PLC. But the studies on epidemiology of Primary Live Cancer in Shunde were seldom reported. The risk factors of PLC were not identify .So, it was necessary explore risk factors of PLC in Shunde City and this work had a certain realistic significance.
Purposes:
To performed a case-control study to explore risk factors of PLC, to research the association between genetic polymorphisms of the human tumor necrosis factor-α-308 position and susceptibility to PLC, and to probe the interaction between environmental and genetic factors in hepatocarcinogenesis by applying molecular biological technology .
To analyse the birth orders of PLC cases, trying to know the relative roles of environmental and genetic factors in Hepatocarcinogenesis.
Objects and methods:
Subjects were PLC patient in hospital from 2004 to 2007 and sibling who lived in Shunde above 10 years. The controls who didn't have PLC, not blood relation with patient at the same village, same sex, age±3 years, living in Shunde above 10 years.
The contents of survey include:(1) Questionnaire: general conditions;personal history of smoking, drinking,eating, drink water,disease status, birth order, etc;(2)Laboratory examination:○1 to detect HBV, HCV,AFP, liver fluke by ELISA .○2 to analyze TNF-α-308 position by PCR-RELP.
We first applied conditional logistic regression analysis to explore the main effects and interactional effects of HBV, smoking, drinking,TNF2in hepatocarcinogenesis. Then we analyzed the birth orders of PLC cases.
Results:
(1) The frequencies of allele TNF2 were significant differences between case group and control group (P=0.012), with the OR of 2.67 (95%CI: 1.24-5.74).
(2) Applied conditional logistic regression to explore risk factors of PLC , Hepatitis B, alcohol consumption, liver desease history were associated with increased risks of PLC in this study.
(3) HBsAg was interacted with the TNF2 allele during the generation of PLC, With the OR=19.83(95%CI:4.20-93.61); their RERI were 14.39, their API were 0.7253,their SI were 4.23.
(4) Liver desease history was interacted with the TNF2 allele during the generation of PLC, With the OR=7.63(95 %CI:1.05-67.71),their RERI were 2.22, their API were 0.29,their SI were 1.50.
(5) Alcohol consumption was interacted with the TNF2 allele during the generation of PLC, With the OR=4.57(95 %CI:1.62-12.88),their RERI were 1.39, their API were 0.30,their SI were 1.63.
(6) No relation was found between birth order and pathogenesis of PLC in the patient of HBsAg (-),but in the patient of HBsAg(+) birth order had relation with pathogenesis of PLC.
Conclusion:
(1) There was association between genetic polymorphisms of the human tumor necrosis factor-α-308 position and PLC; the TNF2 allele was susceptibility to PLC.
(2) Applied conditional logistic regression to explore risk factors of PLC , Hepatitis B, alcohol consumption, liver desease history were associated with increased risks of PLC in this study.
(3) The TNF2 allele was interacted with HBsAg, liver desease history, alc-ohol consumption.
(4) Hepatitis B played more important role than genetic factors in hepatica-rcinogenes in Shunde.But control Hepatitis B, genetic factors would play important role in hepatocarcinogenesis .
引文
[1] 吴盂超,沈锋.肝癌研究的现状和进展.国外医学肿瘤学分册,2000,27(1):17-19.
[2] Stewart BW, Kleihues P. World Cancer Report[M].Lyon:IARC,2003.1-351.
[3] 1991 年中国卫生事业发展情况统计公报.
[4] Yang L, Parkin DM, Ferlay J, et al. Estimates of cancer incidence in China for 2000 and projection for 2005.Cancer Epidemiology, Biomarkers & Prevention. 2005,14(1):243-250.
[5] 广东佛山顺德区慢性病防治中心.顺德区恶性肿瘤防治工作总结[R].2006,12.
[6] 顾公望,周汉高.肝癌研究病因的共识.世界肿瘤杂志,2002,1(1):1-3.
[7] 沈福民,胡应.原发性肝细胞癌的家庭聚集性研究.中国优生与遗传杂志,1995,3:74-78.
[8] Shen FM, Lee MK, Gong HM, et al. Complex Segregation Analysis of Primary Hepatocellular Carcinoma in Chinese Families: Interaction of Inherited Susceptibility and Hepatitis B Viral Infection. Am J Hum Genet,1991,49:88.
[9] Block TM, Mehta AS, Fimmel CJ, et al. Molecular viral oncology of hepatocellular carcinoma.Oncogene,2003,22(33):5093～5107.
[10] 沈福民,孟炜,倪鹏生.遗传流行病学.见:沈福民,主编.流行病学原理与方法.第1 版.上海:上海医科大学出版社,2001,186-196.
[11] 王育新,章友康,朱世乐,等.肿瘤坏死因子的基因多态性与系统性红斑狼疮的相关性分析.中华医学杂志,1998,78(2):111-114.
[12] 范列英,仲人前,屠小卿,等.肿瘤坏死因子α基因多态性与中国人自身免疫肝病相关性研究.中华肝脏病杂志,2004,12(3):160-163.
[13] 陈会,左武,李艳,等.湖北地区汉族人群TNF基因多态性分布研究.微循环学杂志, 2002,12(1):18-20.
[14] 何铭均,陈盛强,林云潮,等.广东汉族人肿瘤坏死因子A-308基因多态性.广州医药, 2005, 36(5):61-62.
[15] 郑芳.TNF-a结构与功能的关系.国外医学免疫学分册,2OO3,26(2):60-63.
[16] Wilson AG, Symons JA, Mcodowell TI, et al. Effects of polymorphism in the human tumor necrosis factor-α promoter on transcriptional activation Proc Natl Acad,1997,94:3195-3199.
[17] Abraham LJ, Kroeger KM. Impact of the-308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. Leukoc Biol, 1999,66:562–566.
[18] Danis VA, Millington M, Hyland V, et al.Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis Markers, 1994, 12:127-133.
[19] Wheelhouse NM,Chart YS,Gillies SE,et a1.TNF-alpha induced DNA damage in primary murine hepatoeytes.Int J Mol Med,2003,12(6):889-894.
[20] Sheng-Yow Ho, Ying-Jan Wang, Hen-Li Chen, et al. 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, 2004,15: 657-664.
[21] Jeng Jen-Eing, Tsai Jung-Fa, Chuang Lee-Yea, et a1.Tumor Necrosis Factor-α 308.2 Polymorphism Is Associated with Advanced Hepatic Fibrosis and Higher Risk for Hepatocellular Carcinoma. Neoplasia,2007,9(11):987-992.
[22] Yue Wang, Naoya Kato, Yu Jin, et al.Interleukin-1 beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology,2003,1:66-69.
[23] Migitak K,Miyazoe S,Maeda Y,et al.Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection-association between TGF beta1 polymorphisms and hepatocellular carcinoma.Hepatol,2005,42(4):505- 510.
[24] Warzocha K, Ribeiro P, Bienvenu J, et al. Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome. Blood 1998,91:3574-3581.
[25] Davies FE, Rollinson SJ, Fawstron AC, et al. High-producer haplotypesof tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment. Clin Oncol,2000,18:2843-2851.
[26] Wu S,Rodabough K,Martine MO,eta1.Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-l. interleukin-6 and tumor factor-alpha. Obstet Gynoco1,1992,166(3):997-999.
[27] Hirano F, Komura K, Fukawa E, et al Tumor necrosis factor alpha (TNF-alpha) -induced RANTES chemokine expression via activation of NF-kappa B and p38 MAP kinase:roles of TNF-a in alcoholic liver diseases.J Hepatol,2003,38(4)∶483.
[28] Knight B, Yeoh GC, Husk KL, et al. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice.J Exp Med,2000,192(12):1809～1818.
[29] Suganuma M, Okabe S, Marino MW ,et al .Essential role of tumor necrosis factor alpha (TNF-alpha) in tumorpromotion as revealed by TNF-alpha-deficient mice. Cancer Res, 1999,59(18):4516-4518.
[30] Wheelhouse NM, Chan YS, Gillies SE, et al TNF-alpha induced DNA danage in primary marine hepatocytes. lnt J Mol Med,2004,12(6):889-894.
[31] 边中启,汪伟业,秦一中,等.肿瘤坏死因子诱发鸭乙型肝炎病毒感染雏鸭急性肝坏死的实验研究.中华传染病杂志.1992,10(2):88.
[32] 梅小平,敬雪明,曾跃,等.重型肝炎患者血清肿瘤坏死因子-α、白细胞介素-6和白细胞介素-8水平的变化及其与HBV DNA间的相互关系,临床内科杂志,2006,23 (5):320-323.
[33] 苏是苍,李承彬,胡勤明.慢性乙肝肝纤维化不同分期TNF-α、NO和内毒素水平变化.标记免疫分析与临床,2006,13(3):131-132.
[34] Gonzalez S, Rodrigo L, Martinez Borra J, et al. TNF-alpha-308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease [J].Am J Gastroentero,2003,98(5):1101-1106.
[35] Louis E, FranchincontD, Piron A, et al Tumour necrosis factor(TNF) genepolymorphism influences TNF-alpha production in lipopolysaccharide (LPS)- stimulated whole blood cell culture in healthy humans. Clin Exp Immuno,1998, 113(3):401-406.
[36] Kroeger KM, Carviue KS, Abraham LJ, et al. The-308 tumor necrosis factor-alpha promoter polymorphism effects transcription.Mol Immuno,1997, 34(5):391-399.
[37] 哀淑芳,张跃新,单鑫,等.肿瘤坏死因子α、Caspase-3、核因子-κβmRNA 在病毒性肝炎中的表达与肝细胞凋亡.中华肝脏病杂志,2006,14(2):129-131.
[38] 杨季云,张思仲,郭红,等.肿瘤坏死因子α通过激活NF-κB信号通路加快肝细胞周期进程.生物化学与生物物理进展,2007,34(6):604-610.
[39] Webber EM, Wu JC, Wang L, et a1.Overexpression of transforming growth factor—alpha causes liver enlargement and increased hepatocyte proliferation in transgenic mice. Am J Pathol,1994,145(2):398—408.
[40] 丁小东,范建高.肥胖性脂肪肝发病机制的研究进展.肝脏,2003,8 (4):52-54.
[41]Yang SQ.Lin HZ,Jiaw.et a1.Hepatic Hyperplasia in Noncirrhotic Fatty Livers is Obesity—related Hepatic Steatosis a Premalignant Condition.Cancer Research, 2001,61(1):50I6-5023.
[42]范建高,徐正捷,王国良,等.高脂饮食致大鼠非酒精性脂肪性肝炎肝纤维化模型.世界华人消化杂志,2002,10(4):392-396.
[43] Ariel E, Feldstein, Nathan W, et a1. Free fatty acids promote hepatic lipotoxicity by stimulating TNF expression via a lysosomal pathway. Hepatology, 2004,40(1):185-194.
[44] 钱燕,范建高.TNF-α在非酒精性脂肪性肝病中的作用及其机制.国际消化病杂志,2006,26(4):266-269.
[45] Valenti L, Fracanzani A,Dongiovanni P, et a1.Tumor necrosis factor a promoter polymorphisms and insulin presistance in non alcoholic fatty liver disease.Gastroenterology,2002,122(2):274—280.
[46] 周永健,李瑜元,聂玉强,等.肿瘤坏死因子-α基因多态性与非酒精性脂肪性肝病的关系.中华消化杂志,2006,26(5):311-315.
[47] Simeonova PP,Gallucci RM,Huldemmn T,et a1.The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride[J].Toxicol Appl Pharmacolcol 2001,177(2):112-120.
[48] 陈伟锋,汪谦,张可飞,等. 肿瘤坏死因子-α对肝星状细胞形态及表达结缔组织生长因子的影响[J]. 中华实验外科杂志,2005,22(8):922-925.
[49] 林菊生,程元桥,田德英.HLA—DRB 1 和肿瘤坏死因-α基因多态性与肝硬化的遗传易感性[J].中华内科杂志,2002,41(12):818-822.
[50] Tokushige K,Tsuchiya N,Hasegawa K,et a1. Influence of TNF gene polymorphism and HLA—DRB 1 haplotype in Japanese patients with chronic liver disease caused by HCV.Am J Gastroenterol,2003,98:l60一l66.
[51] Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunological Review, 2000, 174: 250-259.
[52] Mukaiya M,Nishi M,Miyake H,et a1.Chronic liver diseases for the risk of hepatocellular carcinoma:a ease2control study in Japan:etiology association of alcohol consumption, cigarette smoking and the development of chronic liver disease.Hepatogastroenterology,1998,45:2328-2334.
[53]吴金明,王思元,梁扩寰.大鼠酒精性肝损害时血浆细胞因子TNF-α、IL一6水平的变化及其意义.胃肠病学和肝病学杂志,2002,11(2):115-117.
[54] Yin M,Wheeler MD,Kono H,et a1.Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice.Gastroentero1ogy,1999,117(4):942—952.
[55]森本道雄,姚桢.酒精性肝损伤的最新研究进展.日本医学介绍,1997,18(10): 447-449.
[56]Yot suyanagi H, Hashidume K, Suzuki M, et a1.Role of Hepatitis B Virus in Hepatocarcinogenesis in Alcoholics.Alcohol Clin ExpRcs,2004,28(8):181-184.
[57].Zhou Z,Wang L,Song Z,et a1. A Critical Involvement of Oxidative Stress in Acute Alcohol-Induced Hepatic TNF-α Production.Am J Patho1,2003,163:1137-1146.
[58]Kroemer G,Dallaporta B,Resche-Rigon M.The mitochondrial death/life regulator in apoptosis ang necrosis.Annu Rev Physiol,1998,60:619-642.
[59] PriceJ, HareE. Birth order studies: some sources of bias.Br J Psychiatry, 1969,115: 633-646.
[60] 王志瑾,周元平,程兵.广东省顺德市原发性肝癌危险因素流行病学研究.中华流行病学杂志,l996,17(3):141-144.
[61] 蔡如琳,盂炜,陆鸿雁,等.原发性肝癌与出生顺序的研究.中华流行病学杂志, 2003,24 (1):22-24.
[62] 俞顺章,赵宁,姿晓林,等.饮水中微囊藻毒素与我国原发性肝癌关系的研究.中华肿瘤杂志,2001,23:96-99.
[63] Kuper H, Hsieh C, Stuver SO, et al. Birth order, as a proxy for age at infection, In the etiology of hepatocellular carcinoma.Epidemiology,2000, 11:680-683.
[64] Yao JL.Perinatal transmission of hepatitis B virus infection and vaccination in China .Gut.1996,38 (2): 37-38.
[65] 曹燕燕,边建超.洛阳市肝癌的出生顺序分析.复旦学报,2005,32(4):447-451.
[66]汤伯明,边建超,王其军,等.洛阳市肝癌危险因素的病例对照研究.现代预防医学,2002,20:723-725.
[2] Stewart BW, Kleihues P. World Cancer Report[M].Lyon:IARC,2003.1-351.
[3] 1991 年中国卫生事业发展情况统计公报.
[4] Yang L, Parkin DM, Ferlay J, et al. Estimates of cancer incidence in China for 2000 and projection for 2005.Cancer Epidemiology, Biomarkers & Prevention. 2005,14(1):243-250.
[5] 广东佛山顺德区慢性病防治中心.顺德区恶性肿瘤防治工作总结[R].2006,12.
[6] 顾公望,周汉高.肝癌研究病因的共识.世界肿瘤杂志,2002,1(1):1-3.
[7] 沈福民,胡应.原发性肝细胞癌的家庭聚集性研究.中国优生与遗传杂志,1995,3:74-78.
[8] Shen FM, Lee MK, Gong HM, et al. Complex Segregation Analysis of Primary Hepatocellular Carcinoma in Chinese Families: Interaction of Inherited Susceptibility and Hepatitis B Viral Infection. Am J Hum Genet,1991,49:88.
[9] Block TM, Mehta AS, Fimmel CJ, et al. Molecular viral oncology of hepatocellular carcinoma.Oncogene,2003,22(33):5093～5107.
[10] 沈福民,孟炜,倪鹏生.遗传流行病学.见:沈福民,主编.流行病学原理与方法.第1 版.上海:上海医科大学出版社,2001,186-196.
[11] 王育新,章友康,朱世乐,等.肿瘤坏死因子的基因多态性与系统性红斑狼疮的相关性分析.中华医学杂志,1998,78(2):111-114.
[12] 范列英,仲人前,屠小卿,等.肿瘤坏死因子α基因多态性与中国人自身免疫肝病相关性研究.中华肝脏病杂志,2004,12(3):160-163.
[13] 陈会,左武,李艳,等.湖北地区汉族人群TNF基因多态性分布研究.微循环学杂志, 2002,12(1):18-20.
[14] 何铭均,陈盛强,林云潮,等.广东汉族人肿瘤坏死因子A-308基因多态性.广州医药, 2005, 36(5):61-62.
[15] 郑芳.TNF-a结构与功能的关系.国外医学免疫学分册,2OO3,26(2):60-63.
[16] Wilson AG, Symons JA, Mcodowell TI, et al. Effects of polymorphism in the human tumor necrosis factor-α promoter on transcriptional activation Proc Natl Acad,1997,94:3195-3199.
[17] Abraham LJ, Kroeger KM. Impact of the-308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. Leukoc Biol, 1999,66:562–566.
[18] Danis VA, Millington M, Hyland V, et al.Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis Markers, 1994, 12:127-133.
[19] Wheelhouse NM,Chart YS,Gillies SE,et a1.TNF-alpha induced DNA damage in primary murine hepatoeytes.Int J Mol Med,2003,12(6):889-894.
[20] Sheng-Yow Ho, Ying-Jan Wang, Hen-Li Chen, et al. 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, 2004,15: 657-664.
[21] Jeng Jen-Eing, Tsai Jung-Fa, Chuang Lee-Yea, et a1.Tumor Necrosis Factor-α 308.2 Polymorphism Is Associated with Advanced Hepatic Fibrosis and Higher Risk for Hepatocellular Carcinoma. Neoplasia,2007,9(11):987-992.
[22] Yue Wang, Naoya Kato, Yu Jin, et al.Interleukin-1 beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology,2003,1:66-69.
[23] Migitak K,Miyazoe S,Maeda Y,et al.Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection-association between TGF beta1 polymorphisms and hepatocellular carcinoma.Hepatol,2005,42(4):505- 510.
[24] Warzocha K, Ribeiro P, Bienvenu J, et al. Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome. Blood 1998,91:3574-3581.
[25] Davies FE, Rollinson SJ, Fawstron AC, et al. High-producer haplotypesof tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment. Clin Oncol,2000,18:2843-2851.
[26] Wu S,Rodabough K,Martine MO,eta1.Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-l. interleukin-6 and tumor factor-alpha. Obstet Gynoco1,1992,166(3):997-999.
[27] Hirano F, Komura K, Fukawa E, et al Tumor necrosis factor alpha (TNF-alpha) -induced RANTES chemokine expression via activation of NF-kappa B and p38 MAP kinase:roles of TNF-a in alcoholic liver diseases.J Hepatol,2003,38(4)∶483.
[28] Knight B, Yeoh GC, Husk KL, et al. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice.J Exp Med,2000,192(12):1809～1818.
[29] Suganuma M, Okabe S, Marino MW ,et al .Essential role of tumor necrosis factor alpha (TNF-alpha) in tumorpromotion as revealed by TNF-alpha-deficient mice. Cancer Res, 1999,59(18):4516-4518.
[30] Wheelhouse NM, Chan YS, Gillies SE, et al TNF-alpha induced DNA danage in primary marine hepatocytes. lnt J Mol Med,2004,12(6):889-894.
[31] 边中启,汪伟业,秦一中,等.肿瘤坏死因子诱发鸭乙型肝炎病毒感染雏鸭急性肝坏死的实验研究.中华传染病杂志.1992,10(2):88.
[32] 梅小平,敬雪明,曾跃,等.重型肝炎患者血清肿瘤坏死因子-α、白细胞介素-6和白细胞介素-8水平的变化及其与HBV DNA间的相互关系,临床内科杂志,2006,23 (5):320-323.
[33] 苏是苍,李承彬,胡勤明.慢性乙肝肝纤维化不同分期TNF-α、NO和内毒素水平变化.标记免疫分析与临床,2006,13(3):131-132.
[34] Gonzalez S, Rodrigo L, Martinez Borra J, et al. TNF-alpha-308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease [J].Am J Gastroentero,2003,98(5):1101-1106.
[35] Louis E, FranchincontD, Piron A, et al Tumour necrosis factor(TNF) genepolymorphism influences TNF-alpha production in lipopolysaccharide (LPS)- stimulated whole blood cell culture in healthy humans. Clin Exp Immuno,1998, 113(3):401-406.
[36] Kroeger KM, Carviue KS, Abraham LJ, et al. The-308 tumor necrosis factor-alpha promoter polymorphism effects transcription.Mol Immuno,1997, 34(5):391-399.
[37] 哀淑芳,张跃新,单鑫,等.肿瘤坏死因子α、Caspase-3、核因子-κβmRNA 在病毒性肝炎中的表达与肝细胞凋亡.中华肝脏病杂志,2006,14(2):129-131.
[38] 杨季云,张思仲,郭红,等.肿瘤坏死因子α通过激活NF-κB信号通路加快肝细胞周期进程.生物化学与生物物理进展,2007,34(6):604-610.
[39] Webber EM, Wu JC, Wang L, et a1.Overexpression of transforming growth factor—alpha causes liver enlargement and increased hepatocyte proliferation in transgenic mice. Am J Pathol,1994,145(2):398—408.
[40] 丁小东,范建高.肥胖性脂肪肝发病机制的研究进展.肝脏,2003,8 (4):52-54.
[41]Yang SQ.Lin HZ,Jiaw.et a1.Hepatic Hyperplasia in Noncirrhotic Fatty Livers is Obesity—related Hepatic Steatosis a Premalignant Condition.Cancer Research, 2001,61(1):50I6-5023.
[42]范建高,徐正捷,王国良,等.高脂饮食致大鼠非酒精性脂肪性肝炎肝纤维化模型.世界华人消化杂志,2002,10(4):392-396.
[43] Ariel E, Feldstein, Nathan W, et a1. Free fatty acids promote hepatic lipotoxicity by stimulating TNF expression via a lysosomal pathway. Hepatology, 2004,40(1):185-194.
[44] 钱燕,范建高.TNF-α在非酒精性脂肪性肝病中的作用及其机制.国际消化病杂志,2006,26(4):266-269.
[45] Valenti L, Fracanzani A,Dongiovanni P, et a1.Tumor necrosis factor a promoter polymorphisms and insulin presistance in non alcoholic fatty liver disease.Gastroenterology,2002,122(2):274—280.
[46] 周永健,李瑜元,聂玉强,等.肿瘤坏死因子-α基因多态性与非酒精性脂肪性肝病的关系.中华消化杂志,2006,26(5):311-315.
[47] Simeonova PP,Gallucci RM,Huldemmn T,et a1.The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride[J].Toxicol Appl Pharmacolcol 2001,177(2):112-120.
[48] 陈伟锋,汪谦,张可飞,等. 肿瘤坏死因子-α对肝星状细胞形态及表达结缔组织生长因子的影响[J]. 中华实验外科杂志,2005,22(8):922-925.
[49] 林菊生,程元桥,田德英.HLA—DRB 1 和肿瘤坏死因-α基因多态性与肝硬化的遗传易感性[J].中华内科杂志,2002,41(12):818-822.
[50] Tokushige K,Tsuchiya N,Hasegawa K,et a1. Influence of TNF gene polymorphism and HLA—DRB 1 haplotype in Japanese patients with chronic liver disease caused by HCV.Am J Gastroenterol,2003,98:l60一l66.
[51] Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunological Review, 2000, 174: 250-259.
[52] Mukaiya M,Nishi M,Miyake H,et a1.Chronic liver diseases for the risk of hepatocellular carcinoma:a ease2control study in Japan:etiology association of alcohol consumption, cigarette smoking and the development of chronic liver disease.Hepatogastroenterology,1998,45:2328-2334.
[53]吴金明,王思元,梁扩寰.大鼠酒精性肝损害时血浆细胞因子TNF-α、IL一6水平的变化及其意义.胃肠病学和肝病学杂志,2002,11(2):115-117.
[54] Yin M,Wheeler MD,Kono H,et a1.Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice.Gastroentero1ogy,1999,117(4):942—952.
[55]森本道雄,姚桢.酒精性肝损伤的最新研究进展.日本医学介绍,1997,18(10): 447-449.
[56]Yot suyanagi H, Hashidume K, Suzuki M, et a1.Role of Hepatitis B Virus in Hepatocarcinogenesis in Alcoholics.Alcohol Clin ExpRcs,2004,28(8):181-184.
[57].Zhou Z,Wang L,Song Z,et a1. A Critical Involvement of Oxidative Stress in Acute Alcohol-Induced Hepatic TNF-α Production.Am J Patho1,2003,163:1137-1146.
[58]Kroemer G,Dallaporta B,Resche-Rigon M.The mitochondrial death/life regulator in apoptosis ang necrosis.Annu Rev Physiol,1998,60:619-642.
[59] PriceJ, HareE. Birth order studies: some sources of bias.Br J Psychiatry, 1969,115: 633-646.
[60] 王志瑾,周元平,程兵.广东省顺德市原发性肝癌危险因素流行病学研究.中华流行病学杂志,l996,17(3):141-144.
[61] 蔡如琳,盂炜,陆鸿雁,等.原发性肝癌与出生顺序的研究.中华流行病学杂志, 2003,24 (1):22-24.
[62] 俞顺章,赵宁,姿晓林,等.饮水中微囊藻毒素与我国原发性肝癌关系的研究.中华肿瘤杂志,2001,23:96-99.
[63] Kuper H, Hsieh C, Stuver SO, et al. Birth order, as a proxy for age at infection, In the etiology of hepatocellular carcinoma.Epidemiology,2000, 11:680-683.
[64] Yao JL.Perinatal transmission of hepatitis B virus infection and vaccination in China .Gut.1996,38 (2): 37-38.
[65] 曹燕燕,边建超.洛阳市肝癌的出生顺序分析.复旦学报,2005,32(4):447-451.
[66]汤伯明,边建超,王其军,等.洛阳市肝癌危险因素的病例对照研究.现代预防医学,2002,20:723-725.