炎性体信号通路相关microRNA多态性和NEIL2基因多态性与食管癌的相关性研究
摘要
目的
通过流行病学调查,分析饮食与环境等相关因素与闽南地区食管癌发病之间的关系,探讨炎性体信号通路相关miRNA多态性和NEIL2基因多态性对食管癌个体易感性的影响,从分子水平探讨食管癌的发病机理和早期诊断标志,为制订闽南地区食管癌的综合防制措施提供科学依据。
方法
1、采用以医院为基础的病例对照研究设计,收集334名食管癌病例,与等数的性别、年龄(±3岁)频数匹配的对照,通过调查问卷获取生活环境和饮食习惯等信息,采用非条件logistic回归模型评价食管癌的危险因素,计算OR及其95%CI。
2、应用分子流行病学研究方法,采用两阶段病例对照设计,采集病例与对照的外周血,提取DNA,以MALDI-TOF-MS质谱检测技术对炎性体信号通路相关microRNA多态性进行检测,采用Log_addivit(e共显性模型)、Dominate model(显性模型)、Recessive model(隐性模型)三种模型来进行分析。用非条件Logistic回归模型分析基因多态性与食管癌风险的比值比OR及其95%可信区间(CI),用Haploview和PHASE推断单体型频率及其对食管癌的影响。
3、应用分子流行病学研究方法,采用病例对照设计,采集病例与对照的外周血,提取DNA,先测序寻找闽南地区人群常见NEIL2多态位点,然后以MALDI-TOF-MS质谱检测技术对NEIL2多态位点进行检测,采用Log_addivite、Dominate model、Recessive model三种模型来进行分析。用非条件Logistic回归模型分析基因多态性与食管癌风险的比值比OR及其95%可信区间(CI),用Haploview和PHASE推断单体型频率及其对食管癌的影响。
结果
1、闽南地区人群食管癌的危险因素有:接触有害物质OR=1.840(95% CI:1.202～2.186)、日吸烟量≥20支OR=1.397(95%CI:1.130～1.726)、食用霉变食物OR=2.246(95%CI:1.258～4.011);食管癌的保护因素有:用餐时间大于10分钟OR=0.741(95% CI:0.556～0.987)、食用油类型OR=0.610(95% CI:0.529～0.703)、使用冰箱OR=0.567(95%CI:0.376～0.853)、食用水果OR=0.603(95% CI:0.490～0.743)。
2、在炎性体信号通路相关microRNA多态性与食管癌的两阶段病例对照研究中未发现有意义的多态位点。在分层分析中发现在大于60岁的人群中,在Recessive model下rs829314呈保护因素,OR为0.39(95%CI:0.16-0.94);rs477813可能也呈保护因素,OR为0.41(95% CI 0.17-1.00)。
3、发现闽南地区人群碱基切除修复基因NEIL2两个常见的多态位点rs8191613和rs8191664,经病例对照研究验证,这两个位点及其所构成的单体型在食管癌患者和健康对照中的差别无统计学意义。但在分层分析中,Dominate model模型下rs8191613在吸烟的人群中呈危险因素,OR为1.60(95% CI:1.04-2.48),这表明在食管癌的发生中可能存在基因-环境的交互作用。
结论
1、常接触农药、化肥等有害物质、日吸烟量≥20支、食用霉变食物为食管癌的主要危险因素;用餐时间大于10分钟、食用调和油、茶油、使用冰箱、经常食用水果为食管癌的主要保护因素。
2、炎性体信号通路相关microRNA多态性中rs829314位点在大于60岁的人群中,Recessive model下呈保护因素。
3、rs8191613和rs8191664为闽南地区人群碱基切除修复基因NEIL2两个常见的多态位点,Dominate model模型下rs8191613在吸烟的人群中呈危险因素,在食管癌的发生中可能存在基因-环境的交互作用。
Objective
By performing the epidemiological survey in Southern Fujian Province where exhibits a high incidence of esophageal cancer,to investigate the risk factors of esophageal cancer;to explore the relationship between MicroRNA polymorphism,inflammatory pathway,NEIL2 gene polymorphism,and esophageal cancer. From molecular level to discussion the pathogenesis and early diagnosis signs of esophageal cancer.The results will provide new insight into the etiology and thus the prevention of this carcinoma.
Methords
1、Using a hospital-based case-control study inculding 334 cases and 335 controls frequency-matched to the cases on age(±3 years) and gender were recuited,and surveyed by questionare.Using unconditional logistic regression model to evaluate risk factors,OR and 95%CI were computed.
2、Designing molecular epidemiology study,peripheral blood of cases and controls were collected,and then their DNA were extracted.Inflammatory pathway related MicroRNA polymorphism were genotyped by MALDI-TOF-MS.Using Log_addivite、Dominate model、Recessive model three genetic models and unconditional logistic regression model to evaluate risks,OR and 95%CI were computed.Haplotype frequencies were computed by Haploview and PHASE software.
3、Designing molecular epidemiology study,peripheral blood of cases and controls were collected,and then their DNA were extracted. First sequencing looking for common SNPs of NEIL2 , then the SNPs were genotyped by MALDI-TOF-MS.Using Log_addivite、Dominate model、Recessive model three genetic models and unconditional logistic regression model to evaluate risks,OR and 95%CI were computed.Haplotype frequencies were computed by Haploview and PHASE software.
Results
1、Risk factors of esophageal cancer included:Contact harmful substances OR=1.840(95% CI:1.202～2.186)、smoked an average of 20 cigarettes a day OR=1.397(95% CI:1.130～1.726)、eat mildew food OR=2.246(95% CI:1.258～4.011);protective factors of esophageal cancer included:dinner time≥10 min OR=0.741(95% CI:0.556～0.987)、Cooking oil type OR=0.610(95% CI:0.529～0.703)、Use the refrigerator OR=0.567(95% CI:0.376～0.853)、Eat more fruit OR=0.603(95% CI:0.490～0.743)。
2、Did not find meaningful polymorphic loci in Inflammatory pathway related MicroRNA polymorphism.But in stratified analysis rs829314 under Recessive model presents protective factor in more than 60 years of the population,OR is 0.39(95% CI:0.16-0.94);rs829314 also may presents protective factor in more than 60 years of the population,OR is 0.41(95% CI:0.17-1.00).
3、Found two common SNPs of basal excision repair gene NEIL2,rs8191613and rs8191664.But Verified by case-control study,they had no relationship with esophageal cancer. But in stratified analysis rs8191613 under Dominate model presents risk factor in smoking population,OR is 1.60(95%CI:1.04-2.48). It indicated that esophageal cancer may exist gene-environment interaction.
Conclusion
1、Risk factors of esophageal cancer included:Contact harmful substances:chemical fertilizer and pesticide、smoked an average of 20 cigarettes a day、eat mildew food;protective factors of esophageal cancer included:dinner time≥10 min、Cooking oil is camellia oil and blend oil、Use the refrigerator、Eat more fruit。
2、Inflammatory pathway related miRNA rs829314 in stratified analysis under Recessive model presents protective factor in more than 60 years of the population.
3、Found two common SNPs of basal excision repair gene NEIL2,rs8191613and rs8191664.Rs8191613 under Dominate model presents risk factor in smoking population.It indicated that esophageal cancer may exist gene-environment interaction.
通过流行病学调查,分析饮食与环境等相关因素与闽南地区食管癌发病之间的关系,探讨炎性体信号通路相关miRNA多态性和NEIL2基因多态性对食管癌个体易感性的影响,从分子水平探讨食管癌的发病机理和早期诊断标志,为制订闽南地区食管癌的综合防制措施提供科学依据。
方法
1、采用以医院为基础的病例对照研究设计,收集334名食管癌病例,与等数的性别、年龄(±3岁)频数匹配的对照,通过调查问卷获取生活环境和饮食习惯等信息,采用非条件logistic回归模型评价食管癌的危险因素,计算OR及其95%CI。
2、应用分子流行病学研究方法,采用两阶段病例对照设计,采集病例与对照的外周血,提取DNA,以MALDI-TOF-MS质谱检测技术对炎性体信号通路相关microRNA多态性进行检测,采用Log_addivit(e共显性模型)、Dominate model(显性模型)、Recessive model(隐性模型)三种模型来进行分析。用非条件Logistic回归模型分析基因多态性与食管癌风险的比值比OR及其95%可信区间(CI),用Haploview和PHASE推断单体型频率及其对食管癌的影响。
3、应用分子流行病学研究方法,采用病例对照设计,采集病例与对照的外周血,提取DNA,先测序寻找闽南地区人群常见NEIL2多态位点,然后以MALDI-TOF-MS质谱检测技术对NEIL2多态位点进行检测,采用Log_addivite、Dominate model、Recessive model三种模型来进行分析。用非条件Logistic回归模型分析基因多态性与食管癌风险的比值比OR及其95%可信区间(CI),用Haploview和PHASE推断单体型频率及其对食管癌的影响。
结果
1、闽南地区人群食管癌的危险因素有:接触有害物质OR=1.840(95% CI:1.202～2.186)、日吸烟量≥20支OR=1.397(95%CI:1.130～1.726)、食用霉变食物OR=2.246(95%CI:1.258～4.011);食管癌的保护因素有:用餐时间大于10分钟OR=0.741(95% CI:0.556～0.987)、食用油类型OR=0.610(95% CI:0.529～0.703)、使用冰箱OR=0.567(95%CI:0.376～0.853)、食用水果OR=0.603(95% CI:0.490～0.743)。
2、在炎性体信号通路相关microRNA多态性与食管癌的两阶段病例对照研究中未发现有意义的多态位点。在分层分析中发现在大于60岁的人群中,在Recessive model下rs829314呈保护因素,OR为0.39(95%CI:0.16-0.94);rs477813可能也呈保护因素,OR为0.41(95% CI 0.17-1.00)。
3、发现闽南地区人群碱基切除修复基因NEIL2两个常见的多态位点rs8191613和rs8191664,经病例对照研究验证,这两个位点及其所构成的单体型在食管癌患者和健康对照中的差别无统计学意义。但在分层分析中,Dominate model模型下rs8191613在吸烟的人群中呈危险因素,OR为1.60(95% CI:1.04-2.48),这表明在食管癌的发生中可能存在基因-环境的交互作用。
结论
1、常接触农药、化肥等有害物质、日吸烟量≥20支、食用霉变食物为食管癌的主要危险因素;用餐时间大于10分钟、食用调和油、茶油、使用冰箱、经常食用水果为食管癌的主要保护因素。
2、炎性体信号通路相关microRNA多态性中rs829314位点在大于60岁的人群中,Recessive model下呈保护因素。
3、rs8191613和rs8191664为闽南地区人群碱基切除修复基因NEIL2两个常见的多态位点,Dominate model模型下rs8191613在吸烟的人群中呈危险因素,在食管癌的发生中可能存在基因-环境的交互作用。
Objective
By performing the epidemiological survey in Southern Fujian Province where exhibits a high incidence of esophageal cancer,to investigate the risk factors of esophageal cancer;to explore the relationship between MicroRNA polymorphism,inflammatory pathway,NEIL2 gene polymorphism,and esophageal cancer. From molecular level to discussion the pathogenesis and early diagnosis signs of esophageal cancer.The results will provide new insight into the etiology and thus the prevention of this carcinoma.
Methords
1、Using a hospital-based case-control study inculding 334 cases and 335 controls frequency-matched to the cases on age(±3 years) and gender were recuited,and surveyed by questionare.Using unconditional logistic regression model to evaluate risk factors,OR and 95%CI were computed.
2、Designing molecular epidemiology study,peripheral blood of cases and controls were collected,and then their DNA were extracted.Inflammatory pathway related MicroRNA polymorphism were genotyped by MALDI-TOF-MS.Using Log_addivite、Dominate model、Recessive model three genetic models and unconditional logistic regression model to evaluate risks,OR and 95%CI were computed.Haplotype frequencies were computed by Haploview and PHASE software.
3、Designing molecular epidemiology study,peripheral blood of cases and controls were collected,and then their DNA were extracted. First sequencing looking for common SNPs of NEIL2 , then the SNPs were genotyped by MALDI-TOF-MS.Using Log_addivite、Dominate model、Recessive model three genetic models and unconditional logistic regression model to evaluate risks,OR and 95%CI were computed.Haplotype frequencies were computed by Haploview and PHASE software.
Results
1、Risk factors of esophageal cancer included:Contact harmful substances OR=1.840(95% CI:1.202～2.186)、smoked an average of 20 cigarettes a day OR=1.397(95% CI:1.130～1.726)、eat mildew food OR=2.246(95% CI:1.258～4.011);protective factors of esophageal cancer included:dinner time≥10 min OR=0.741(95% CI:0.556～0.987)、Cooking oil type OR=0.610(95% CI:0.529～0.703)、Use the refrigerator OR=0.567(95% CI:0.376～0.853)、Eat more fruit OR=0.603(95% CI:0.490～0.743)。
2、Did not find meaningful polymorphic loci in Inflammatory pathway related MicroRNA polymorphism.But in stratified analysis rs829314 under Recessive model presents protective factor in more than 60 years of the population,OR is 0.39(95% CI:0.16-0.94);rs829314 also may presents protective factor in more than 60 years of the population,OR is 0.41(95% CI:0.17-1.00).
3、Found two common SNPs of basal excision repair gene NEIL2,rs8191613and rs8191664.But Verified by case-control study,they had no relationship with esophageal cancer. But in stratified analysis rs8191613 under Dominate model presents risk factor in smoking population,OR is 1.60(95%CI:1.04-2.48). It indicated that esophageal cancer may exist gene-environment interaction.
Conclusion
1、Risk factors of esophageal cancer included:Contact harmful substances:chemical fertilizer and pesticide、smoked an average of 20 cigarettes a day、eat mildew food;protective factors of esophageal cancer included:dinner time≥10 min、Cooking oil is camellia oil and blend oil、Use the refrigerator、Eat more fruit。
2、Inflammatory pathway related miRNA rs829314 in stratified analysis under Recessive model presents protective factor in more than 60 years of the population.
3、Found two common SNPs of basal excision repair gene NEIL2,rs8191613and rs8191664.Rs8191613 under Dominate model presents risk factor in smoking population.It indicated that esophageal cancer may exist gene-environment interaction.
引文
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[51]郭强,孔毅荣,付玲,等.炎性体研究进展[J].军事医学科学院院刊,2007, 31(5):490-493.
[52]马昭君,易洪刚,赵杨,陈峰.全基因组关联研究中的二阶段病例对照设计[J].中华流行病学杂志,2010,31(10):1184-1187.
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[1]Parkin DM,Bray FI,Devesa SS.Cancer burden in the year 2000[J].The global picture.Eur J Cancer 2001;37 Suppl 8:S4-S66.
[2]Sarah B Umar and David E Fleischer.Esophageal cancer epidemiology,pathogenesis and prevention[J].NATURE CLINICAl PRACTICE GASTROENTEROLOGY & HEPATOLOGY,2008;5(9):517-526.
[3]CANCERMondial.Globocan 2002[EB/OL]. http://www.dep.iarc.fr/.
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[1]Parkin DM,Bray FI,Devesa SS.Cancer burden in the year 2000[J].The global picture.Eur J Cancer 2001;37 Suppl 8:S4-S66.
[2]Sarah B Umar and David E Fleischer.Esophageal cancer epidemiology,pathogenesis and prevention[J].NATURE CLINICAl PRACTICE GASTROENTEROLOGY & HEPATOLOGY,2008;5(9):517-526.
[3]CANCERMondial.Globocan 2002[EB/OL]. http://www.dep.iarc.fr/.
[4]Blot WJ , McLaughlin JK.The changing epidemiology of esophageal cancer[J].Semin Oncol 1999,26:2-8.
[5] Espey DK,et al.(2007) Annual report to the nation on the status of cancer,1975-2004,featuring cancer in American Indians and Alaska Natives[J]. Cancer 110:2119-2152.
[6]中华人民共和国卫生部.前十位恶性肿瘤死亡率[EB/OL]. http://www.moh.gov.cn/publicfiles/business/htmlfiles/zwgkzt/ptjnj/year2009/t-9.htm ,2009.
[7]Freedman ND et al.(2007)A prospective study of tobacco,alcohol,and the risk of esophageal and gastric cancer subtypes[J].Am J Epidemiol 165:1424-1433.
[8]Zambon P,Talamini R,La Vecchia C,et al.Smoking,type of alcoholic beverage and squamous cell esophageal cancer in northern Italy[J].Int J Cancer,2000,86(1):144-149.
[9]李克,于萍,朱远锋,等.中国南方沿海食管癌高发区危险因素研究:吸烟作用[J].肿瘤,2002,22(2):96-98.
[10]Gammon MD et al.(1997)Tobacco,alcohol,and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia[J]. J Natl Cancer Inst 89:1277-1284.
[11]RA Woutersen,LM Appelman,A Van Garderen-Hoetmer,et al.Inhalation toxicity of acetaldehyde in rats.Ⅲ.Carcinogenicity study[J].Toxicology,1986,41:213-31.
[12]李文杰.食管癌高发区居民膳食营养素摄入水平分析[J].中国肿瘤,1996,5(l0):16-17.
[13]陆建邦,连士勇,孙喜斌,等.林州食管癌流行动态与居民膳食结构变化调查报告[J].中国公共卫生,2001,17(1):60-61.
[14]李铭新,季川,等.林县酸菜中苯并芘的初步分析[J].中华肿瘤杂志1981,3(4):303.
[15]季川,李铭新.林县酸菜及玉米面中天然存在的亚硝胺[J].中华肿瘤杂志,1983,5:73.
[16]王明耀,等.林县酸菜中亚硝基化台物(Roussin红甲酯)及其前体物的分析[J].肿瘤防治研究,1983;10:l2.
[17]刘桂亭,刘天舟.河南省食管癌病因学研究[J].中国肿瘤,2000,9(5):220-221.
[18]候俊,乔翠云.河北省磁县食管癌危险因素病例对照研究[J].中国肿瘤,1999,8(6):41.
[19]陆士新.我国对食管癌研究的贡献[J].首都医药,1998,5(4):14-15.
[20]陆士新,崔小邢,姜伟,等.亚硝胺诱发人胎儿食管上皮癌和人食管癌基因的研究[J].中国肿瘤,1992,1(12):10.
[21]Syrjanen KJ.Histological changes identical to those of condylomatous lesions found in esophageal squamous cell carcinomas[J].Arch Geschwulstforsch 1982,52:283-292.
[22]Shen ZY, Hu SP, Lu LC, Tang CZ, Kuang ZS, Zhong SP, Zeng Y. Detection of human papillomavirus in esophageal carcinoma[J]. J Med Virol 2002,68:412-416.
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