先天免疫炎症因子IL-1B、IL-1RN、TNF-A单核苷酸多态与新疆地区维、汉民族胃癌相关性及其预后的研究
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摘要
目的：
胃癌(Gastric cancer)是最常见的恶性肿瘤之一,其死亡率位居全球恶性肿瘤死亡率的第二位,居中国恶性肿瘤死亡率的首位。虽然随着诊断和治疗水平的提高,胃癌的发病率和死亡率近年在全球范围内,特别是在部分发达国家中呈逐年下降的趋势,但仍然是威胁人类健康的主要疾病,预后很差,5年生存率仅为10%-19%。胃癌的发生是环境和遗传因素共同作用的结果,其确切的发病机制尚不明确。流行病学、遗传学和临床医学等研究发现了多个生物和社会因素可能会导致胃癌发生的危险性增加,但是有些危险因素在不同国家、地区和不同人群中的结果尚不一致；除与研究的样本量、不同人群的社会经济状况等因素有关外,还由于胃癌的发生具有地域分布和种族差异的特点。维吾尔族是新疆的主要少数民族,与汉族有着不同的遗传背景、生活习惯和饮食方式,这都与胃癌的发生密切相关。因此,了解同一地区不同民族胃癌发病的危险因素,可为新疆不同民族胃癌的病因研究及一级预防提供科学的理论依据。胃癌的发生过程中,不同个体对环境暴露的反应存在易感性,而其中与免疫炎症反应相关的细胞因子遗传多态性可以部分解释不同个体感染H.pylori后胃粘膜炎症反应程度及其发展结局的差异,并由此将基因多态性、H.pylori感染与胃癌发生的关系联系起来,因此倍受关注。IL-1B、IL-1RN和TNF-A三个基因均为与免疫炎症反应相关基因,已有研究结果表明它们与胃癌的发生密切相关,并且具有种族和地区差异性。但在维吾尔族人群中尚未见报道。因此,本研究探讨先天免疫炎症因子基因变异在新疆维吾尔族、汉族胃癌发生中的作用,识别维吾尔族和汉族胃癌不同易感基因群,探讨不同民族胃癌易感性差异机制；同时,结合患者的临床资料,探讨基因的遗传多态在胃癌预后中所起的作用,为胃癌的综合防治及个体化诊断和治疗提供依据。
方法：
1)采用病例-对照研究方法,收集2007-2009年间新发的、由新疆医科大学附属肿瘤医院经病理学确诊的原发性胃癌患者322例,其中维吾尔族93例,汉族229例。选择与病例无血缘关系、同民族、同性别、年龄相差±5岁、同期体检的健康人群487例作为对照人群,其中维吾尔族231例,汉族256例。对其进行问卷调查,对胃癌发病的环境危险因素采用logistic回归方法进行分析并进一步估算其人群归因危险度；
2)以第一部分调查人群为基础,采用Snapshot技术进行IL-1B基因3个SNPs位点：rs1143630C>A、rs1143633A>G、rs3136558T>C; IL-1RN基因1个SNPs位点：rs315952C>T; TNF-A基因2个SNPs位点：rs1800629G>A、rs361525G>A基因分型,单体型构建采用SHEsis软件进行预测和分析；
3)以第一部分调查人群为基础,选择其中随访资料完整的原发性胃癌病例共计253例,其中维族73例,汉族180例。采用COX比例风险模型进行胃癌预后多因素生存分析。
结果：
1)胃炎、胃溃疡、家族史、饮酒、缺少锻炼、进食速度快、喜食硬饭、经常吃油炸／火烤食品、H.pylori阳性为维吾尔族胃癌发生的主要危险因素,经常饮茶、新鲜蔬菜摄入量>500g/日、经常吃洋葱、水果是保护因素,这13个因素的综合人群归因危险度为78.07%；而在汉族人群中,胃溃疡、家族史、吸烟、喜食咸饭、H.pylori阳性为其发生胃癌的主要危险因素,经常饮茶、经常喝牛奶、经常吃洋葱、水果为保护因素,这9个因素的综合人群归因危险度为64.79%。
2)在维吾尔族人群中,IL-1B、IL-1RN和TNF-A基因各SNP位点不论是等位基因位点、基因型还是单体型在病例组和对照组中的分布频率均无统计学意义(P>0.05)。
3)在汉族人群中,IL-1B基因rs3136558位点CC+CT基因型在病例组和对照组的分布有统计学意义(X2=12.50,P=0.000),即携带C等位基因者发生胃癌的风险降低(OR=0.51,95%CI：0.35-0.74)。TNF-A基因rs361525位点AA+GA基因型在病例组和对照组之间的分布有统计学意义(X2=4.56,P=0.03),即携带A等位基因者发生胃癌的风险增加(OR=2.41,95%CI：1.06-5.49)。其余基因不同位点基因型与胃癌之间未发现有关联。在汉族人群中,A-G-T单体型和C-G-C单体型在病例组和对照组分布频率分别为0.20%和0.25%、0.03%和0.07%,差异有统计学意义(X2=4.70,P=0.03和X2=5.81,P=0.02),TNF-A基因A-A单体型在病例组及对照组分布频率分别为0.92%和0.86%,差异有统计学意义(X2=7.03,P=0.01)。
4)基因-基因之间的联合作用表明,在汉族人群中,同时携带IL-1B基因rs3136558 TT基因型与TNF-A rs361525GA+AA基因型的个体发生胃癌的危险性是同时携带IL-1B基因rs3136558 CT+CC基因型与TNF-A rs361525GG基因型的个体的3.36倍(95%CI：1.26-9.23),是同时携带IL-1B基因rs3136558 CT+CC基因型与TNF-A rs361525GG基因型的个体的1.90倍(95%CI.1.34-2.95)。
5)H.pylori感染与基因之间的交互作用表明,在汉族人群中,H.pylori感染阳性,同时携带IL-1基因rs3136558 TT基因型个体发生胃癌的危险性是H.pylori感染阴性并携带IL-1基因rs3136558 CT+CC基因型个体的2.25倍(95%CI：1.37-3.69)。H.pylori感染阳性并携带TNF-A rs361525GA+AA基因型个体、H.pylori感染阳性并携带TNF-A rs361525 GG基因型个体发生胃癌的危险性分别是H.pylori阴性同时携带TNF-A rs361525 GG基因型个体发生胃癌危险性的4.01倍(95%CI：1.50-10.85)和1.98倍(95%CI：1.36-2.88)。
6)肿瘤的分化程度、浸润深度、临床分期对维吾尔族胃癌患者的预后有影响,可以作为判断维吾尔族胃癌患者预后的独立指标。在汉族胃癌患者中,除肿瘤的分化程度、浸润深度、临床分期三个影响预后的因素外,TNF-A rs361525位点基因型也是影响汉族胃癌患者预后的独立指标,即携带TNF-A rs361525 GA+AA基因型的胃癌患者不良预后的风险是GG基因型的患者的1.310倍(95%CI:1.009～2.641)。
结论：
1)维吾尔族和汉族胃癌发病危险因素存在一定差别,结果提示可根据不同的民族采取不同的防治措施。
2) IL-1B、TNF-A基因单核苷酸多态、基因-基因之间及H.pylori感染-基因之间存在的交互作用与汉族胃癌发病风险相关,这种相关性具有民族差异。
3) TNF-A基因单核苷酸多态对汉族胃癌预后有一定的影响,这种影响在民族之间的表现不同。
Objective:
Gastric cancer (GC) is one of the common malignant tumors and had a high incidence and mortality rate in the world and ranked second in mortality. Gastric cancer is the leading cause of malignant tumor death among Chinese population. Due to increased levels of diagnosis and treatment of gastric cancer, the morbidity and mortality of gastric cancer showed a declining trend in the world in recent years, especially in some developed countries, however, it is still a major disease impelling the health of the people. The prognosis of gastric cancer is very poor and 5-year survival rate is only 10%-19%. The occurrence of gastric cancer is a result from the combined role of multiple factors, including environmental factors, genetic factors, and so on. Until now, the precise mechanism of gastric cancer is uncertainty. Studies on epidemiology, genetics and clinical medicine found that multiple biological and social factors may increase risk of gastric cancer, while some risk factors are not consistent in different countries, regions and populations. Besides the factors of sample size and socio-economic conditions, geographical distribution and characteristics of ethnic play an important part in the incidence of gastric cancer. Uygur is the main minority in Xinjiang, and it has different genetic background, lifestyle and dietary patterns from Han nationality, which are closely related with the incidence of gastric cancer. Therefore, the studies about risk factors of gastric cancer of the different ethnic groups in the same area may provide a scientific theory in the etiology and primary prevention. In the progress of gastric cancer, different individuals exposed the same environmental risk factors exist the different susceptibility. And the genetic polymorphisms of cytokines associated with immune inflammation were considered to be risk factors relevant to the degree of inflammation in gastric mucosal and the development of gastric cancer. In recent year, many researches focused on the relationship between inflammatory cytokine gene polymorphisms, H.pylori infections and gastric cancer. Some researches revealed that immune inflammation related gene IL-1B, IL-1RN, TNF-A has correlation with the developing of gastric cancer, and geographical distribution and characteristics of ethnic play an important role. However, the related studies had not been found in Uygur populations. Therefore, we designed to investigate the inflammatory cytokine gene polymorphisms and gastric cancer susceptibility in Uygur and Han nationalities, to clarify the risk SNPs of gastric cancer in Uygur and Han populations, to discuss the mechanism of gastric cancer susceptibility in different ethnic groups. Meanwhile, we explored the relationship between genetic polymorphism and gastric prognosis so as to provide evidences for making the integrated preventive measures and individualized diagnosis and treatment.
Methods:
1) A case-control study was conducted.322 gastric cancer cases were newly diagnosed by histopathology in Affiliated Tumor Hospital of Xinjiang Medical University from 2007 to 2009 which included 93 Uygur populations and 229 Han populations.487 controls included 231 Uygur populations and 256 Han populations were selected from the health examination clinics as the same time as the cases. The control group should satisfy the requirement below:having no blood relationship with the cases, the same race, the same sex, the age distance within±5 years old. All subjects were surveyed with the same questionnaire. The logistic regression analysis about the environmental risk factors of gastric cancer was carried out by SPSS 15.0 statistical package and further PAR was also assessed.
2) Based on the first part subjects, the polymorphisms of IL-1B gene at rs1143630C >A site, rs1143633A>G site, rs3136558T>C site and IL-1RN gene at rs315952C>T site and TNF-A gene at rs1800629G>A site, rs361525G>A site were detected by Snapshot methods. Haplotype block was determined and inferred by SHEsis software.
3) Based on the first part subjects,253 patients were followed-up completely which included 73 Uygur populations and 180 Han populations. The prognostic factors were evaluated using the Cox regression proportional hazard model.
Results:
1) In Uygur populations, the risk factors of GC included gastritis, gastric ulcer, family history of gastric cancer, alcohol drinking, lacking exercise, fast eating, solid meal, often intaking fried food, over consumption of salt, H.pylori infections, and the protective factors of GC were drinking tea, intaking vegetables and eating onion and fruits. The integrated PAR of 13 factors was 78.07%in Uygur. The environmental risk factors of gastric cancer in Han populations were gastric ulcer, family history of GC, smoking, over consumption of salt, H.pylori infections, and the protective factors of GC were drinking tea, drinking milk, often eating onion and fruits. The integrated PAR of 9 factors was 64.79%.
2) In Uygur populations, allele, genotype and haplotype of IL-IB, IL-1RN, TNF-A gene have no significantly difference in gastric cancer and control group (P>0.05).
3) In Han populations, there was significant difference in the frequencies of IL-IB gene at rs3136558 site CC+CT genotype between cases and controls X2=12.50, P=0.000). The individuals with C allele can decrease risk of developing GC (OR=0.51,95%C7: 0.35-0.74). There was significant difference in the frequencies of TNF-A gene at rs361525 site AA+GA genotype between cases and controls (X2=4.56, P=0.03). The individuals with A allele can increase risk of developing GC (OR=2.41,95%CI: 1.06-5.49).In Han populations, the frequencies of haplotype A-G-T, C-G-C were 0.20%, 0.25%and 0.03%,0.07%in cases and controls respectively, and there were significant difference between cases and controls (X2=4.70, P=0.03 and x2=5-81, P=0.02). The frequencies of TNF-A gene haplotype A-A were 0.92%and 0.86%in cases and controls respectively, and there were significant difference between cases and controls (x2=7.03, P=0.01).
4) In Han populations, the further analysis of the combining effect between gene and gene showed that individuals having IL-IB gene at rs3136558 site TT genotype and TNF-A gene at rs361525 site GA+AA genotype had a 3.36-fold (95%CI:1.26-9.23) increased risk of developing GC compared with those who having IL-IB gene at rs3136558 site CT+CC genotype and TNF-A gene at rs361525 site GG genotype.
5) In Han populations, interaction action between H.pylori infections and gene showed that individuals having IL-IB gene at rs3136558 site TT genotype and H.pylori infections had a 2.25-fold (95%C7:1.37-3.69) increased risk of developing GC compared with those who having CT+CC genotype but no H.pylori infections. Individuals having TNF-A gene at rs361525 site GA+AA genotype and H.pylori infections had a 4.01-fold (95%CI:1.50-10.85) increased risk of developing GC compared with those who having GG genotype but no H.pylori infections, individuals having TNF-A gene at rs361525 site GG genotype and H.pylori infections had a 1.98-fold (95%C7:1.36-2.88) increased risk of developing GC compared with those who having GG genotype but no H.pylori infections.
6) The prognosis of gastric cancer in Uygur populations is influenced by degree of tumor differentiation, depth of invasion, advanced stage which can consider as independent indicators of the prognosis of gastric cancer. In Han cases, besides the factors of degree of tumor differentiation, depth of invasion, advanced stage, the genotypes of TNF-A gene at rs361525 site is also an independent indicator of the prognosis of gastric cancer. The cases having TNF-A gene at rs361525 site GA+AA genotype had a 1.31-fold (95%CI:1.009-2.641) increased risk of patients with poor prognosis compared with those who having GG genotype.
Conclusion:
1) Different risk factors of gastric cancer were existed in Uygur and Han populations, and different ethnic groups can adopt different preventive measures.
2) It is possible that incidence of gastric cancer in Han population is associated with the genetic polymorphism of IL-1B, TNF-A and the interaction action between gene and gene, H.pylori infections and gene, and this association exists ethnic diversity.
3) The prognosis of gastric cancer is influenced by the genetic polymorphism of TNF-A in Han populations, and this affect has been expressed differently in ethnic groups.
胃癌(Gastric cancer)是最常见的恶性肿瘤之一,其死亡率位居全球恶性肿瘤死亡率的第二位,居中国恶性肿瘤死亡率的首位。虽然随着诊断和治疗水平的提高,胃癌的发病率和死亡率近年在全球范围内,特别是在部分发达国家中呈逐年下降的趋势,但仍然是威胁人类健康的主要疾病,预后很差,5年生存率仅为10%-19%。胃癌的发生是环境和遗传因素共同作用的结果,其确切的发病机制尚不明确。流行病学、遗传学和临床医学等研究发现了多个生物和社会因素可能会导致胃癌发生的危险性增加,但是有些危险因素在不同国家、地区和不同人群中的结果尚不一致；除与研究的样本量、不同人群的社会经济状况等因素有关外,还由于胃癌的发生具有地域分布和种族差异的特点。维吾尔族是新疆的主要少数民族,与汉族有着不同的遗传背景、生活习惯和饮食方式,这都与胃癌的发生密切相关。因此,了解同一地区不同民族胃癌发病的危险因素,可为新疆不同民族胃癌的病因研究及一级预防提供科学的理论依据。胃癌的发生过程中,不同个体对环境暴露的反应存在易感性,而其中与免疫炎症反应相关的细胞因子遗传多态性可以部分解释不同个体感染H.pylori后胃粘膜炎症反应程度及其发展结局的差异,并由此将基因多态性、H.pylori感染与胃癌发生的关系联系起来,因此倍受关注。IL-1B、IL-1RN和TNF-A三个基因均为与免疫炎症反应相关基因,已有研究结果表明它们与胃癌的发生密切相关,并且具有种族和地区差异性。但在维吾尔族人群中尚未见报道。因此,本研究探讨先天免疫炎症因子基因变异在新疆维吾尔族、汉族胃癌发生中的作用,识别维吾尔族和汉族胃癌不同易感基因群,探讨不同民族胃癌易感性差异机制；同时,结合患者的临床资料,探讨基因的遗传多态在胃癌预后中所起的作用,为胃癌的综合防治及个体化诊断和治疗提供依据。
方法：
1)采用病例-对照研究方法,收集2007-2009年间新发的、由新疆医科大学附属肿瘤医院经病理学确诊的原发性胃癌患者322例,其中维吾尔族93例,汉族229例。选择与病例无血缘关系、同民族、同性别、年龄相差±5岁、同期体检的健康人群487例作为对照人群,其中维吾尔族231例,汉族256例。对其进行问卷调查,对胃癌发病的环境危险因素采用logistic回归方法进行分析并进一步估算其人群归因危险度；
2)以第一部分调查人群为基础,采用Snapshot技术进行IL-1B基因3个SNPs位点：rs1143630C>A、rs1143633A>G、rs3136558T>C; IL-1RN基因1个SNPs位点：rs315952C>T; TNF-A基因2个SNPs位点：rs1800629G>A、rs361525G>A基因分型,单体型构建采用SHEsis软件进行预测和分析；
3)以第一部分调查人群为基础,选择其中随访资料完整的原发性胃癌病例共计253例,其中维族73例,汉族180例。采用COX比例风险模型进行胃癌预后多因素生存分析。
结果：
1)胃炎、胃溃疡、家族史、饮酒、缺少锻炼、进食速度快、喜食硬饭、经常吃油炸／火烤食品、H.pylori阳性为维吾尔族胃癌发生的主要危险因素,经常饮茶、新鲜蔬菜摄入量>500g/日、经常吃洋葱、水果是保护因素,这13个因素的综合人群归因危险度为78.07%；而在汉族人群中,胃溃疡、家族史、吸烟、喜食咸饭、H.pylori阳性为其发生胃癌的主要危险因素,经常饮茶、经常喝牛奶、经常吃洋葱、水果为保护因素,这9个因素的综合人群归因危险度为64.79%。
2)在维吾尔族人群中,IL-1B、IL-1RN和TNF-A基因各SNP位点不论是等位基因位点、基因型还是单体型在病例组和对照组中的分布频率均无统计学意义(P>0.05)。
3)在汉族人群中,IL-1B基因rs3136558位点CC+CT基因型在病例组和对照组的分布有统计学意义(X2=12.50,P=0.000),即携带C等位基因者发生胃癌的风险降低(OR=0.51,95%CI：0.35-0.74)。TNF-A基因rs361525位点AA+GA基因型在病例组和对照组之间的分布有统计学意义(X2=4.56,P=0.03),即携带A等位基因者发生胃癌的风险增加(OR=2.41,95%CI：1.06-5.49)。其余基因不同位点基因型与胃癌之间未发现有关联。在汉族人群中,A-G-T单体型和C-G-C单体型在病例组和对照组分布频率分别为0.20%和0.25%、0.03%和0.07%,差异有统计学意义(X2=4.70,P=0.03和X2=5.81,P=0.02),TNF-A基因A-A单体型在病例组及对照组分布频率分别为0.92%和0.86%,差异有统计学意义(X2=7.03,P=0.01)。
4)基因-基因之间的联合作用表明,在汉族人群中,同时携带IL-1B基因rs3136558 TT基因型与TNF-A rs361525GA+AA基因型的个体发生胃癌的危险性是同时携带IL-1B基因rs3136558 CT+CC基因型与TNF-A rs361525GG基因型的个体的3.36倍(95%CI：1.26-9.23),是同时携带IL-1B基因rs3136558 CT+CC基因型与TNF-A rs361525GG基因型的个体的1.90倍(95%CI.1.34-2.95)。
5)H.pylori感染与基因之间的交互作用表明,在汉族人群中,H.pylori感染阳性,同时携带IL-1基因rs3136558 TT基因型个体发生胃癌的危险性是H.pylori感染阴性并携带IL-1基因rs3136558 CT+CC基因型个体的2.25倍(95%CI：1.37-3.69)。H.pylori感染阳性并携带TNF-A rs361525GA+AA基因型个体、H.pylori感染阳性并携带TNF-A rs361525 GG基因型个体发生胃癌的危险性分别是H.pylori阴性同时携带TNF-A rs361525 GG基因型个体发生胃癌危险性的4.01倍(95%CI：1.50-10.85)和1.98倍(95%CI：1.36-2.88)。
6)肿瘤的分化程度、浸润深度、临床分期对维吾尔族胃癌患者的预后有影响,可以作为判断维吾尔族胃癌患者预后的独立指标。在汉族胃癌患者中,除肿瘤的分化程度、浸润深度、临床分期三个影响预后的因素外,TNF-A rs361525位点基因型也是影响汉族胃癌患者预后的独立指标,即携带TNF-A rs361525 GA+AA基因型的胃癌患者不良预后的风险是GG基因型的患者的1.310倍(95%CI:1.009～2.641)。
结论：
1)维吾尔族和汉族胃癌发病危险因素存在一定差别,结果提示可根据不同的民族采取不同的防治措施。
2) IL-1B、TNF-A基因单核苷酸多态、基因-基因之间及H.pylori感染-基因之间存在的交互作用与汉族胃癌发病风险相关,这种相关性具有民族差异。
3) TNF-A基因单核苷酸多态对汉族胃癌预后有一定的影响,这种影响在民族之间的表现不同。
Objective:
Gastric cancer (GC) is one of the common malignant tumors and had a high incidence and mortality rate in the world and ranked second in mortality. Gastric cancer is the leading cause of malignant tumor death among Chinese population. Due to increased levels of diagnosis and treatment of gastric cancer, the morbidity and mortality of gastric cancer showed a declining trend in the world in recent years, especially in some developed countries, however, it is still a major disease impelling the health of the people. The prognosis of gastric cancer is very poor and 5-year survival rate is only 10%-19%. The occurrence of gastric cancer is a result from the combined role of multiple factors, including environmental factors, genetic factors, and so on. Until now, the precise mechanism of gastric cancer is uncertainty. Studies on epidemiology, genetics and clinical medicine found that multiple biological and social factors may increase risk of gastric cancer, while some risk factors are not consistent in different countries, regions and populations. Besides the factors of sample size and socio-economic conditions, geographical distribution and characteristics of ethnic play an important part in the incidence of gastric cancer. Uygur is the main minority in Xinjiang, and it has different genetic background, lifestyle and dietary patterns from Han nationality, which are closely related with the incidence of gastric cancer. Therefore, the studies about risk factors of gastric cancer of the different ethnic groups in the same area may provide a scientific theory in the etiology and primary prevention. In the progress of gastric cancer, different individuals exposed the same environmental risk factors exist the different susceptibility. And the genetic polymorphisms of cytokines associated with immune inflammation were considered to be risk factors relevant to the degree of inflammation in gastric mucosal and the development of gastric cancer. In recent year, many researches focused on the relationship between inflammatory cytokine gene polymorphisms, H.pylori infections and gastric cancer. Some researches revealed that immune inflammation related gene IL-1B, IL-1RN, TNF-A has correlation with the developing of gastric cancer, and geographical distribution and characteristics of ethnic play an important role. However, the related studies had not been found in Uygur populations. Therefore, we designed to investigate the inflammatory cytokine gene polymorphisms and gastric cancer susceptibility in Uygur and Han nationalities, to clarify the risk SNPs of gastric cancer in Uygur and Han populations, to discuss the mechanism of gastric cancer susceptibility in different ethnic groups. Meanwhile, we explored the relationship between genetic polymorphism and gastric prognosis so as to provide evidences for making the integrated preventive measures and individualized diagnosis and treatment.
Methods:
1) A case-control study was conducted.322 gastric cancer cases were newly diagnosed by histopathology in Affiliated Tumor Hospital of Xinjiang Medical University from 2007 to 2009 which included 93 Uygur populations and 229 Han populations.487 controls included 231 Uygur populations and 256 Han populations were selected from the health examination clinics as the same time as the cases. The control group should satisfy the requirement below:having no blood relationship with the cases, the same race, the same sex, the age distance within±5 years old. All subjects were surveyed with the same questionnaire. The logistic regression analysis about the environmental risk factors of gastric cancer was carried out by SPSS 15.0 statistical package and further PAR was also assessed.
2) Based on the first part subjects, the polymorphisms of IL-1B gene at rs1143630C >A site, rs1143633A>G site, rs3136558T>C site and IL-1RN gene at rs315952C>T site and TNF-A gene at rs1800629G>A site, rs361525G>A site were detected by Snapshot methods. Haplotype block was determined and inferred by SHEsis software.
3) Based on the first part subjects,253 patients were followed-up completely which included 73 Uygur populations and 180 Han populations. The prognostic factors were evaluated using the Cox regression proportional hazard model.
Results:
1) In Uygur populations, the risk factors of GC included gastritis, gastric ulcer, family history of gastric cancer, alcohol drinking, lacking exercise, fast eating, solid meal, often intaking fried food, over consumption of salt, H.pylori infections, and the protective factors of GC were drinking tea, intaking vegetables and eating onion and fruits. The integrated PAR of 13 factors was 78.07%in Uygur. The environmental risk factors of gastric cancer in Han populations were gastric ulcer, family history of GC, smoking, over consumption of salt, H.pylori infections, and the protective factors of GC were drinking tea, drinking milk, often eating onion and fruits. The integrated PAR of 9 factors was 64.79%.
2) In Uygur populations, allele, genotype and haplotype of IL-IB, IL-1RN, TNF-A gene have no significantly difference in gastric cancer and control group (P>0.05).
3) In Han populations, there was significant difference in the frequencies of IL-IB gene at rs3136558 site CC+CT genotype between cases and controls X2=12.50, P=0.000). The individuals with C allele can decrease risk of developing GC (OR=0.51,95%C7: 0.35-0.74). There was significant difference in the frequencies of TNF-A gene at rs361525 site AA+GA genotype between cases and controls (X2=4.56, P=0.03). The individuals with A allele can increase risk of developing GC (OR=2.41,95%CI: 1.06-5.49).In Han populations, the frequencies of haplotype A-G-T, C-G-C were 0.20%, 0.25%and 0.03%,0.07%in cases and controls respectively, and there were significant difference between cases and controls (X2=4.70, P=0.03 and x2=5-81, P=0.02). The frequencies of TNF-A gene haplotype A-A were 0.92%and 0.86%in cases and controls respectively, and there were significant difference between cases and controls (x2=7.03, P=0.01).
4) In Han populations, the further analysis of the combining effect between gene and gene showed that individuals having IL-IB gene at rs3136558 site TT genotype and TNF-A gene at rs361525 site GA+AA genotype had a 3.36-fold (95%CI:1.26-9.23) increased risk of developing GC compared with those who having IL-IB gene at rs3136558 site CT+CC genotype and TNF-A gene at rs361525 site GG genotype.
5) In Han populations, interaction action between H.pylori infections and gene showed that individuals having IL-IB gene at rs3136558 site TT genotype and H.pylori infections had a 2.25-fold (95%C7:1.37-3.69) increased risk of developing GC compared with those who having CT+CC genotype but no H.pylori infections. Individuals having TNF-A gene at rs361525 site GA+AA genotype and H.pylori infections had a 4.01-fold (95%CI:1.50-10.85) increased risk of developing GC compared with those who having GG genotype but no H.pylori infections, individuals having TNF-A gene at rs361525 site GG genotype and H.pylori infections had a 1.98-fold (95%C7:1.36-2.88) increased risk of developing GC compared with those who having GG genotype but no H.pylori infections.
6) The prognosis of gastric cancer in Uygur populations is influenced by degree of tumor differentiation, depth of invasion, advanced stage which can consider as independent indicators of the prognosis of gastric cancer. In Han cases, besides the factors of degree of tumor differentiation, depth of invasion, advanced stage, the genotypes of TNF-A gene at rs361525 site is also an independent indicator of the prognosis of gastric cancer. The cases having TNF-A gene at rs361525 site GA+AA genotype had a 1.31-fold (95%CI:1.009-2.641) increased risk of patients with poor prognosis compared with those who having GG genotype.
Conclusion:
1) Different risk factors of gastric cancer were existed in Uygur and Han populations, and different ethnic groups can adopt different preventive measures.
2) It is possible that incidence of gastric cancer in Han population is associated with the genetic polymorphism of IL-1B, TNF-A and the interaction action between gene and gene, H.pylori infections and gene, and this association exists ethnic diversity.
3) The prognosis of gastric cancer is influenced by the genetic polymorphism of TNF-A in Han populations, and this affect has been expressed differently in ethnic groups.
引文
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