【作者】 杨婕；

【导师】 徐耀初； 沈洪兵；

【作者基本信息】 南京医科大学 ， 流行病与卫生统计学， 2004， 硕士

【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。更多还原

【Abstract】 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 theGenetic Polymorphism of Interleukin-1 β andSusceptibility to Gastric CancerIt 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 controlsThe 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 GCIn 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 GC3. Comparison of IL-1B gene polymorphism in different racesThe 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 HaplotypeThe 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 GeneticPolymorphism of Interleukin-1 Receptor Antagonistand Susceptibility to Gastric CancerInflammation is one of the most important gastric physiologi更多还原