白细胞介素-1基因（IL-1）多态性与胃癌遗传易感性的分子流行病学研究
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摘要
胃癌是全世界最常见的恶性肿瘤之一，病死率高，对人类健康和生命构成严重威胁。尽管其发病率在全球呈普遍下降趋势，但在中国、日本和拉丁美洲地区仍维持较高的发病率和死亡率。在我国，胃癌死亡率高居恶性肿瘤之首。胃癌的病因复杂，研究认为其发生是遗传和环境因素共同作用的结果。因此，深入进行胃癌病因学和分子流行病学研究，寻找和确定相关分子标志物，筛选高危人群以采取有效的预防控制措施已成为当务之急。本课题以江苏省金坛市和淮安市两个胃癌相对高发区为研究现场，开展了以人群为基础的胃癌病例-对照研究和分子流行病学分析。
第一部分：白细胞介素-1β基因(IL-1B)多态性与胃癌遗传易感性关系的研究
IL-1B基因多态性与个体感染幽门螺杆菌后产生的胃酸分泌抑制程度的差异有关，可能影响感染结局和个体患胃癌的风险，但国内外研究结论尚不一致。本研究应用聚合酶链反应和限制性片段长度多态性(PCR-RFLP)技术对IL-1B基因-31、-511和+3954位点多态性与胃癌易感性之间关系进行探讨。主要结果如下：
1、IL-1B各位点基因型在胃癌病例与对照组的分布及其危险度估计
IL-1B基因-31位点野生型纯合子-31CC在病例与对照组中的频率分别为21.8％和27.9％，而突变型纯合子-31TT的频率分别为29.6％和23.3％。调整性别、年龄等混杂因素后，携带-31TT的个体与携带-31CC者比较，其发生胃癌的危险性增加75％(OR=1.75，95％CI=1.08-2.85)。
IL-1B基因-511位点-511TT基因型在病例与对照组中的频率分别为18.2％和24.9％，与之相比较，-511CT和-511CC基因型分别增加
南京医科大学硕士学位论文
46%(OR=1 .46，95%Cl=0.94一2.25)和63%(OR=1 .63，95%Cl=0.98一2.73)
的胃癌危险性，两者均接近统计学显著性水平。
lL一IB基因+3 954位点只发现两种基因型，即+3 954CC和
+3 954CT，且后者的频率较低，在病例和对照组中分别为5.3%和
2.6%。限于样本含量，本研究中+3 954CT基因型虽增加近2倍的患胃
癌危险性，但未达到显著水平(OR=l .93，95%CI=0.77一4.85)。
2、IL一1B各位点基因型与胃癌易感性关系的分层分析
分层分析结果显示:在幽门螺杆菌感染阳性、男性及无胃癌家族
史的人群中，携带IL一IB一3lT和一sllC等位基因与胃癌易感性关系更
为显著。
3、不同种族人群IL一lB各位点基因多态性比较
IL一IB一31位点基因型频率在不同人群和不同研究中差另IJ较大，其
CC型频率最高为75.7%，最低为18.3%，而本次研究为27.9%，与台
湾和日本人群中的一些研究结果接近。
IL一IB一511各位点的基因型频率也存在种族间差异。其中等位基
因T频率在欧洲人群约为35%左右，而亚洲人群则波动于45一50%之
间。在同种族人群中的研究结果较为接近。
亚裔人群IL一lB+3 954基因型频率与欧洲人群差别很大，特另}J是
TT型，例数极少，在本次研究中没有发现一例，CT型频率在10%以
内，而欧洲人群CT型频率接近40%。
4、IL一飞B一31和一511位点连锁不平衡与单倍型分析
遗传连锁分析显示:lL一IB一31和一511位点之间存在连锁不平衡。
对上述两位点单倍型的危险等位基因分析表明:携带3个以上的危险
等位基因可以增加患胃癌的风险的65%(OR=l .65，
95%Cl=1 .01一2.70)。
南京医科大学硕士学位论文
第二部分:白细胞介素一1受体拮抗剂基因(IL一IRN)
多态性与胃癌遗传易感性关系的研究
胃癌的发生是遗传和环境共同作用的结果。炎症反应是幽门螺杆
菌感染胃部后的重要病理生理反应，它可以影响胃炎发展的最终结
局。炎症因子白细胞介素一】受体拮抗剂基因多态性与胃癌遗传易感性
的关系近年来倍受关注，本研究结合聚合酶链反应(PCR)技术的应
用对两者之间关系进行探讨。主要结果如下:
1、IL一IRN各基因型在胃癌病例组与对照组中分布
IL一IRN各基因型在胃癌病例组中分布为1/1型(81.9%)、1/2型
(14.6%)、l/3型(0.7%)、1/4型(1.8%)、2/2型(1.1%):对照组
中的分布为l/l型(81.6%)、l/2型(16.5%)、1/4型(0.8%)、2/2
型(l .2%)。无论何种基因型或其他基因型组合，在病例与对照组间
分布的差异均无显著性。
2、IL一IRN基因多态性和胃癌易感性关系的分层分析
以胃炎史、幽门螺杆菌感染史和胃癌家族史分层，结果显示:与
携带1/1+l/3+1/4型人群相比，携带1/2或2/2型的人群不增加患胃癌
的风险，统计结果差异不显著。
2、不同种族人群IL一IRN基因多态性的比较
本研究显示:中国大陆汉族人群主要以l/l纯合子型为主，频率
为81.6%;其次是l/2杂合子型，为16.5%;2/2纯合子型频率最低为
1.2%。其分布与台湾及大陆其它研究结果相近，而与欧洲人群差异较
大，后者1/1型频率高于50%，而2/2型则接近10%。这表明IL一IRN
基因型在亚裔和欧洲人群中分布有种族差异。
Gastric cancer (GC) is one of the most common tumors in many countries in the world, and its high fatality rate seriously imperil the health of people. Although GC is declining in frequency in the world, its incidence rate still maintain a high level in China, Japan and Latin American areas. In China, GC is the leading cause of cancer death, and its etiology is intricate. Many studies have suggested that environmental and genetic factors may play important roles. So, it is urgent to find out GC etiology and take effective prevention measures. To reach this target, a population-based molecular epidemiological study on GC was conducted in the two high-risk areas of Jintan and Huai'an county of Jiangsu Province.
Part I A Study on the Relationship between the
Genetic Polymorphism of Interleukin-1 β and
Susceptibility to Gastric Cancer
It was reported that interleukin-lB gene polymorphisms were suspected of enhancing production of interleukin-1 β which associated with an increased risk of both hypochlorhydria induced by H.polyri and gastric cancer. Thus, we used PCR-based RFLP analysis to explore the genotype frequencies of polymorphisms in the interleukin-lB (IL-1B) gene promoter region -31, -511 and +3954 loci in gastric cancer cases and cancer-free controls, and evaluate the association between polymorphisms of IL-1B genes and host susceptibility to gastric cancer.
1. The distribution of genotypes of IL-1B in cases and controls
The wild-type homozygote CC genotype frequencies of IL-1B-31 loci were 21.8% and 27.9%, respectively, in cases and controls, and the mutant-type homozygote TT genotype frequencies were 29.6% and 23.3%, respectively. The risk for GC in those with - 3ITT genotype was significantly higher than those with -3ICC genotype, with an adjusted OR of 1.75 (OR=1.75 95%CI=1.08-2.85).
The wild-type homozygote TT genotype frequencies of IL-1B-511 loci were 18.2% and 24.9%, respectively, in cases and controls. Compared to TT genotype, individuals with -511CT and -51 ICC genotypes have a borderline significantly increased risk of gastric cancer (OR=1.46, 95%Cl=0.94-2.25 for -511CT and OR=1.63, 95%CI=0.98-2.73 for -51 ICC, respectively).
We only found two genotypes of +3954CC and +3954CT of 1L-1B+3954 loci. The genotype frequencies of+3954CT were 5.3% and 2.6%, respectively, in cases and controls. Because of the limited sample size, we didn't find significant differences between +3954 loci polymorphisms and risk of gastric cancer( OR=1.93, 95%CI=0.77-4.85 ).
2 A stratified analysis between IL-1B gene polymorphisms and risk factors on GC
In a stratified analysis, significant differences were observed in terms of the associations between IL-1B-31 and -511 loci genotypes and gastric cancer risk for male, individuals with H.polyri infection and without history of GC
3. Comparison of IL-1B gene polymorphism in different races
The genotype frequencies of IL-1B-31 were discrepant in different researches and races. The frequencies of CC genotype were 75.7% in highest, 18.3% in lowest, 27.9% in our study, which were consistent with the results from Japan and Taiwan.
There also existed significant difference among races in IL-1B-511 gene polymorphisms. The frequencies of T allele were about 35% in Europeans and 45%-50% in Asian populations.
The genotype frequencies of IL-1B+3954 in Asian populations had great difference with Europeans especially TT genotype, which didn't been found in our study. The frequency of CT genotype was lower than 10% and the CC genotype was the dominant one.
4.The analysis of Linkage disequilibrium and Haplotype
The results showed that there lied strong Linkage disequilibrium between IL-1B-31 and IL-1B-511, and individuals with three and four haplotype risk genotypes could increase 65% ( OR=1.65 , 95%CI=1.01-2.70 ) risk of getting gastric cancer.
Part n A Study on the Relationship between the Genetic
Polymorphism of Interleukin-1 Receptor Antagonist
and Susceptibility to Gastric Cancer
Inflammation is one of the most important gastric physiologi
第一部分：白细胞介素-1β基因(IL-1B)多态性与胃癌遗传易感性关系的研究
IL-1B基因多态性与个体感染幽门螺杆菌后产生的胃酸分泌抑制程度的差异有关，可能影响感染结局和个体患胃癌的风险，但国内外研究结论尚不一致。本研究应用聚合酶链反应和限制性片段长度多态性(PCR-RFLP)技术对IL-1B基因-31、-511和+3954位点多态性与胃癌易感性之间关系进行探讨。主要结果如下：
1、IL-1B各位点基因型在胃癌病例与对照组的分布及其危险度估计
IL-1B基因-31位点野生型纯合子-31CC在病例与对照组中的频率分别为21.8％和27.9％，而突变型纯合子-31TT的频率分别为29.6％和23.3％。调整性别、年龄等混杂因素后，携带-31TT的个体与携带-31CC者比较，其发生胃癌的危险性增加75％(OR=1.75，95％CI=1.08-2.85)。
IL-1B基因-511位点-511TT基因型在病例与对照组中的频率分别为18.2％和24.9％，与之相比较，-511CT和-511CC基因型分别增加
南京医科大学硕士学位论文
46%(OR=1 .46，95%Cl=0.94一2.25)和63%(OR=1 .63，95%Cl=0.98一2.73)
的胃癌危险性，两者均接近统计学显著性水平。
lL一IB基因+3 954位点只发现两种基因型，即+3 954CC和
+3 954CT，且后者的频率较低，在病例和对照组中分别为5.3%和
2.6%。限于样本含量，本研究中+3 954CT基因型虽增加近2倍的患胃
癌危险性，但未达到显著水平(OR=l .93，95%CI=0.77一4.85)。
2、IL一1B各位点基因型与胃癌易感性关系的分层分析
分层分析结果显示:在幽门螺杆菌感染阳性、男性及无胃癌家族
史的人群中，携带IL一IB一3lT和一sllC等位基因与胃癌易感性关系更
为显著。
3、不同种族人群IL一lB各位点基因多态性比较
IL一IB一31位点基因型频率在不同人群和不同研究中差另IJ较大，其
CC型频率最高为75.7%，最低为18.3%，而本次研究为27.9%，与台
湾和日本人群中的一些研究结果接近。
IL一IB一511各位点的基因型频率也存在种族间差异。其中等位基
因T频率在欧洲人群约为35%左右，而亚洲人群则波动于45一50%之
间。在同种族人群中的研究结果较为接近。
亚裔人群IL一lB+3 954基因型频率与欧洲人群差别很大，特另}J是
TT型，例数极少，在本次研究中没有发现一例，CT型频率在10%以
内，而欧洲人群CT型频率接近40%。
4、IL一飞B一31和一511位点连锁不平衡与单倍型分析
遗传连锁分析显示:lL一IB一31和一511位点之间存在连锁不平衡。
对上述两位点单倍型的危险等位基因分析表明:携带3个以上的危险
等位基因可以增加患胃癌的风险的65%(OR=l .65，
95%Cl=1 .01一2.70)。
南京医科大学硕士学位论文
第二部分:白细胞介素一1受体拮抗剂基因(IL一IRN)
多态性与胃癌遗传易感性关系的研究
胃癌的发生是遗传和环境共同作用的结果。炎症反应是幽门螺杆
菌感染胃部后的重要病理生理反应，它可以影响胃炎发展的最终结
局。炎症因子白细胞介素一】受体拮抗剂基因多态性与胃癌遗传易感性
的关系近年来倍受关注，本研究结合聚合酶链反应(PCR)技术的应
用对两者之间关系进行探讨。主要结果如下:
1、IL一IRN各基因型在胃癌病例组与对照组中分布
IL一IRN各基因型在胃癌病例组中分布为1/1型(81.9%)、1/2型
(14.6%)、l/3型(0.7%)、1/4型(1.8%)、2/2型(1.1%):对照组
中的分布为l/l型(81.6%)、l/2型(16.5%)、1/4型(0.8%)、2/2
型(l .2%)。无论何种基因型或其他基因型组合，在病例与对照组间
分布的差异均无显著性。
2、IL一IRN基因多态性和胃癌易感性关系的分层分析
以胃炎史、幽门螺杆菌感染史和胃癌家族史分层，结果显示:与
携带1/1+l/3+1/4型人群相比，携带1/2或2/2型的人群不增加患胃癌
的风险，统计结果差异不显著。
2、不同种族人群IL一IRN基因多态性的比较
本研究显示:中国大陆汉族人群主要以l/l纯合子型为主，频率
为81.6%;其次是l/2杂合子型，为16.5%;2/2纯合子型频率最低为
1.2%。其分布与台湾及大陆其它研究结果相近，而与欧洲人群差异较
大，后者1/1型频率高于50%，而2/2型则接近10%。这表明IL一IRN
基因型在亚裔和欧洲人群中分布有种族差异。
Gastric cancer (GC) is one of the most common tumors in many countries in the world, and its high fatality rate seriously imperil the health of people. Although GC is declining in frequency in the world, its incidence rate still maintain a high level in China, Japan and Latin American areas. In China, GC is the leading cause of cancer death, and its etiology is intricate. Many studies have suggested that environmental and genetic factors may play important roles. So, it is urgent to find out GC etiology and take effective prevention measures. To reach this target, a population-based molecular epidemiological study on GC was conducted in the two high-risk areas of Jintan and Huai'an county of Jiangsu Province.
Part I A Study on the Relationship between the
Genetic Polymorphism of Interleukin-1 β and
Susceptibility to Gastric Cancer
It was reported that interleukin-lB gene polymorphisms were suspected of enhancing production of interleukin-1 β which associated with an increased risk of both hypochlorhydria induced by H.polyri and gastric cancer. Thus, we used PCR-based RFLP analysis to explore the genotype frequencies of polymorphisms in the interleukin-lB (IL-1B) gene promoter region -31, -511 and +3954 loci in gastric cancer cases and cancer-free controls, and evaluate the association between polymorphisms of IL-1B genes and host susceptibility to gastric cancer.
1. The distribution of genotypes of IL-1B in cases and controls
The wild-type homozygote CC genotype frequencies of IL-1B-31 loci were 21.8% and 27.9%, respectively, in cases and controls, and the mutant-type homozygote TT genotype frequencies were 29.6% and 23.3%, respectively. The risk for GC in those with - 3ITT genotype was significantly higher than those with -3ICC genotype, with an adjusted OR of 1.75 (OR=1.75 95%CI=1.08-2.85).
The wild-type homozygote TT genotype frequencies of IL-1B-511 loci were 18.2% and 24.9%, respectively, in cases and controls. Compared to TT genotype, individuals with -511CT and -51 ICC genotypes have a borderline significantly increased risk of gastric cancer (OR=1.46, 95%Cl=0.94-2.25 for -511CT and OR=1.63, 95%CI=0.98-2.73 for -51 ICC, respectively).
We only found two genotypes of +3954CC and +3954CT of 1L-1B+3954 loci. The genotype frequencies of+3954CT were 5.3% and 2.6%, respectively, in cases and controls. Because of the limited sample size, we didn't find significant differences between +3954 loci polymorphisms and risk of gastric cancer( OR=1.93, 95%CI=0.77-4.85 ).
2 A stratified analysis between IL-1B gene polymorphisms and risk factors on GC
In a stratified analysis, significant differences were observed in terms of the associations between IL-1B-31 and -511 loci genotypes and gastric cancer risk for male, individuals with H.polyri infection and without history of GC
3. Comparison of IL-1B gene polymorphism in different races
The genotype frequencies of IL-1B-31 were discrepant in different researches and races. The frequencies of CC genotype were 75.7% in highest, 18.3% in lowest, 27.9% in our study, which were consistent with the results from Japan and Taiwan.
There also existed significant difference among races in IL-1B-511 gene polymorphisms. The frequencies of T allele were about 35% in Europeans and 45%-50% in Asian populations.
The genotype frequencies of IL-1B+3954 in Asian populations had great difference with Europeans especially TT genotype, which didn't been found in our study. The frequency of CT genotype was lower than 10% and the CC genotype was the dominant one.
4.The analysis of Linkage disequilibrium and Haplotype
The results showed that there lied strong Linkage disequilibrium between IL-1B-31 and IL-1B-511, and individuals with three and four haplotype risk genotypes could increase 65% ( OR=1.65 , 95%CI=1.01-2.70 ) risk of getting gastric cancer.
Part n A Study on the Relationship between the Genetic
Polymorphism of Interleukin-1 Receptor Antagonist
and Susceptibility to Gastric Cancer
Inflammation is one of the most important gastric physiologi
引文
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24. Tseng LH, Chen PJ, Lin MT, et al. Single nucleotide polymorphisms in intron 2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene:
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26. Niu T, Qin ZS, Xu X, et al. Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet. 2002 Jan;70(1): 157-69.
27. Machado JS, Pharoah P, Sousa S, et al. Interleukin-1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology, 2001,121: 823-829
28. Furuta T, El-Omar EM, Xiao F, et al. Interleukin 1β polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology, 2002, 123:92-105
29. Chang YT, Wu MS, Shun CT, et al. Association of polymorphisms of interleukin-1β gene and Helicobacter pylori infection with the risk of gastric ulcer. Hepato-Gastroenterology, 2002, 49:1474-1476
30. Wu MS, Chen CY, Lin MT, et al. Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int. J. Cancer, 2003, 104:617-623
31. Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter pylori and Interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. Journal of the National Cancer Institute, 2002, 94: 1680-1687
32. Kato S, Onda M, Yamada S, et al. Association of the interleukin-1β genetic polymorphism and gastric cancer risk in Japanese. J Gastroenterol, 2001, 36:696-699
33．隋国平，潘凯枫，周彤等．白细胞介素-1β及基因多态性与胃癌发病风险的病例对照研究．中华医学杂志，2003，86(17)：1479-1483
34. Hamajima N, Matsuo K, Saito T, et al. Interleukin 1 polymorphisms, lifestyle factors, and Helicobacter pylori infection. Jpn J Cancer Res. 2001 Apr;92(4):383-9.
35. Arend WP. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest, 1991, 88:1445-1451
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38. Clay FE, Cork MJ, Tarlow JK, et al. Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus. Hum Genet, 1994, 94:407-410
39. Tarlow JK, Clay FE, Cork M J, et al. Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol, 1994,103:387-390
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42. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL-1RN*2) is associated with enhanced IL-1 beta production in vitro. Scand. J. Immunol, 1998, 47: 195-198.
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22. Bidwell JL, et al. Cytokine gene polymorphism in human disease: on-line databases.
23. El-omar EM, Canington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature, 2000, 404:398-402
24. Tseng LH, Chen PJ, Lin MT, et al. Single nucleotide polymorphisms in intron 2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene:
further definition of the IL-1β and IL-1Ra polymorphisms in North American Caucasians and Taiwanese Chinese. Tissue Antigens, 2001, 57:318-324
25. Zeng ZR, Hu PJ, Hu S, et al. Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut, 2003, 52:1684-1689
26. Niu T, Qin ZS, Xu X, et al. Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet. 2002 Jan;70(1): 157-69.
27. Machado JS, Pharoah P, Sousa S, et al. Interleukin-1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology, 2001,121: 823-829
28. Furuta T, El-Omar EM, Xiao F, et al. Interleukin 1β polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology, 2002, 123:92-105
29. Chang YT, Wu MS, Shun CT, et al. Association of polymorphisms of interleukin-1β gene and Helicobacter pylori infection with the risk of gastric ulcer. Hepato-Gastroenterology, 2002, 49:1474-1476
30. Wu MS, Chen CY, Lin MT, et al. Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int. J. Cancer, 2003, 104:617-623
31. Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter pylori and Interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. Journal of the National Cancer Institute, 2002, 94: 1680-1687
32. Kato S, Onda M, Yamada S, et al. Association of the interleukin-1β genetic polymorphism and gastric cancer risk in Japanese. J Gastroenterol, 2001, 36:696-699
33．隋国平，潘凯枫，周彤等．白细胞介素-1β及基因多态性与胃癌发病风险的病例对照研究．中华医学杂志，2003，86(17)：1479-1483
34. Hamajima N, Matsuo K, Saito T, et al. Interleukin 1 polymorphisms, lifestyle factors, and Helicobacter pylori infection. Jpn J Cancer Res. 2001 Apr;92(4):383-9.
35. Arend WP. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest, 1991, 88:1445-1451
36. Arcnd WP. Interleukin 1 receptor antagonist. Adv Immunol, 1993, 54: 167-227
37. Tarlow JK, Blakemore AIF, Lennard A, et al. Polymorphism in the human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of 86-bp tandem repeat. Hum Genet, 1993, 91(4): 403-404
38. Clay FE, Cork MJ, Tarlow JK, et al. Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus. Hum Genet, 1994, 94:407-410
39. Tarlow JK, Clay FE, Cork M J, et al. Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol, 1994,103:387-390
40. Tarlow JK, Cork MJ, Clay FE, et al. Association between interleukin-1 receptor antagonist (IL-lra) gene polymorphism and early and late-onset psoriasis. Br J Dermatol, 1997, 136:132-148
41. Steinkasserer A, Spurr NK, Cox S, et al. The human IL-1 receptor antagonist gene (IL-1RN) maps to chromosome 2q14-q21, in the region of the IL-1 a and IL-1β loci. Genomics, 1992, 13:654-657
42. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL-1RN*2) is associated with enhanced IL-1 beta production in vitro. Scand. J. Immunol, 1998, 47: 195-198.
43. International Agency for Research on Cancer Schistosomes Liver flukes and Helicobacter pylori. IARC Monographs on the Evaltion of
Carcinog Risks to Human Gastric Cancer: Vol 61. Lyon, France: IARC, 1994
44. Halter F, Hurlimann S, Inauen W. Pathophysiology and clinical relevance of Helicobacter pylori. Yale J Biol Med, 1992, 65:625-638
45. Correa P, Fox J, Fontham E. et al. Helicobacter pylori and gastric carcinoma: serum antibody prevalence in population with constrasting cancer risk. Cancer, 1990, 66:2596-2574
46. Miehkje S, Hackelsberger A, Meining A. et al. Histological diagnosis of Helicobacter pylori gastritis is predictive of a high risk of gastric carcinoma. Int J Cancer, 1997, 73:837-839
47. Webb PM, Yu MC, Forman D. et al. An apparent lack of association between Helicobacter pylori infection and risk of gastric cancer in China. Int.J.Cancer. 1996 Sep 4; 67(5): 603-7.
48. Farinati F, Valiante F, Germana B. et al. Prevalence of Helicobacter pylori infection in patients with precancerous changes and gastric cancer. Eur J Cancer Prey. 1993 Jul;2(4):321-6
49. Munoz N, Kato I, Peraza S. et al. Prevalence of precancerous lesions of the stomach in Venezuela. Cancer Epidemiol Biomarkers Prey. 1996 Jan; 5(1):41-6.