XPC基因多态性与肿瘤相关性Meta分析及PAHs致机体早期损伤的危险因素研究

发布时间：2018-03-04 00:26

本文选题：Meta分析　切入点：XPC　出处：《华中科技大学》2008年硕士论文　论文类型：学位论文

【摘要】： 目的和意义:探讨多环芳烃(PAHs)环境外暴露致机体早期生物学损伤,以至最终发展为肿瘤过程中的危险因素,进一步揭示各种环境因子和基因间的复杂关系,为多环芳烃暴露致机体损伤的微观危险度评价提供方法和模式。资料与方法:1. Meta分析:搜索PubMed,EMBASE和中国生物医学(CBM)三个数据库中关于XPC基因多态性(Lys~(939)Gln, PAT-/+,和Ala~(499)Val)和与吸烟相关的肿瘤的研究,共27篇已发表的文献进行meta分析。 2.选取我国东北某大型钢铁公司某焦炉厂焦炉工人166名(暴露组)和该厂职业卫生研究所近3个月未去过焦化厂的69名医护人员(对照组)作为研究对象,测定其尿1-羟基芘浓度,彗星尾距,外周血淋巴细胞微核率,以及细胞色素P4501A1、细胞色素P450 2E1、谷胱甘肽S转移酶P1、环氧化物水化酶、XRCC1、ERCC2基因多态性。用通径分析和BP神经网络模型分析各影响因素与遗传损伤的关系。结果:1. Meta分析:(1)Lys~(939)Gln基因多态性有14个研究共6797名病例和9018名对照,Lys/Gln基因型与癌症总体合并OR=0.99 (95% CI,0.92-1.06),Gln/Gln基因型OR=1.16 (95% CI,1.05-1.28);分层分析,Gln/Gln基因型与肺癌合并OR=1.28 (95% CI,1.07-1.53),在亚洲人群组合并OR=1.21 (95% CI,1.03-1.43)。(2)对Ala~(499)Val基因多态性,10个研究共5581名病例和6351名对照,癌症总体合并OR值分别为:Ala/Val基因型OR=0.94 (95% CI,0.84-1.06)(随机效应模型),Val/Val基因型OR=1.24 (95% CI,1.08-1.42)(固定效应模型);分层分析,Val/Val基因型与膀胱癌合并OR=1.33 (95% CI,1.06-1.68),在高加索人,合并OR=1.41 (95% CI,1.16-1.71)。(3)PAT-/+基因多态性有16个研究共4514名病例和5538名对照, PAT+/-基因型OR = 0.98(95% CI,0.90-1.07),PAT+/+基因型OR = 1.03(95% CI,0.91-1.16)。(4)基因-吸烟交互作用分析显示,在不吸烟者中,携带PAT+/+基因型者患肿瘤的危险度增高(OR = 1.44,95%CI 1.02-2.05;Q检验P = 0.766),而携带PAT-/+基因型的不吸烟者患肿瘤的危险无显著性增加(OR = 0.99,95% CI 0.77-1.26)。 2.通径分析结果表明,焦炉暴露和吸烟均是尿1-OHP浓度的重要影响因素,模型决定系数为0.75;对彗星尾距有显著影响的因素及其作用大小为:尿1-OHP浓度 XRCC1-exon9变异基因型ERCC2-exon10变异基因型XRCC1-exon6变异基因型,模型决定系数为0.22;对CBMN微核率有显著影响的因素及其作用大小为:焦炉暴露尿1-OHP浓度年龄mEH3变异基因型ERCC2-exon10变异基因型XRCC1-exon6变异基因型,模型的决定系数为0.27。 3.所构建的BP神经网络结构为17-8-1,微核的各影响因素中MIV值最大的为焦炉暴露(0.0011),而其它影响相对较大的因素依次为,mEH3变异基因型,ERCC2-exon10变异基因型,XRCC1-exon10变异基因型,是否吸烟,其中mEH3变异基因型对微核起负作用。结论:质量良好的meta分析能在一定程度上弥补分子流行病学分析中样本量不足所带来的缺陷,得出更肯定的结论。XPC基因多态性在肿瘤的发生中有微弱的作用,并且存在基因与吸烟之间的交互作用。外源性因素,尤其是焦炉暴露在机体早期遗传损伤中发挥着重要的作用,其作用大于基因型。通径分析和神经网络模型能担任流行病学中筛选疾病危险因素的任务。
[Abstract]:Purpose: To investigate polycyclic aromatic hydrocarbons (PAHs) exposure to the environment of early biological body injury, and ultimately the development of risk factors in the process of tumor, to reveal the complex relationship between genes and environmental factors, for PAHs exposure injury induced by micro risk assessment method and model.
Materials and methods: 1. Meta analysis: search for PubMed, EMBASE and three databases of Chinese Biomedical Science (CBM), including XPC polymorphism (Lys~ (939) Gln, PAT-/+, Ala~ (499) Val) and smoking related tumors. A total of 27 published literatures were used for meta analysis.
2. from a large Steel Corp in the northeast of China in a coke oven and 166 workers (exposure group) and occupation health research the factory nearly 3 months has not been to the coking plant of 69 medical workers (control group) as the research object, the determination of urinary 1- hydroxypyrene concentrations, comet tail moment, micronucleus of peripheral blood lymphocytes and the rate of cytochrome P4501A1, cytochrome P450 2E1, glutathione S transferase P1, epoxide hydrolase, XRCC1, polymorphism of ERCC2 gene. By path analysis and BP neural network model to analyze the relationship between various factors and genetic damage.
Results: 1. Meta analysis: (1) Lys~ (939) Gln gene polymorphism in 14 studies with a total of 6797 cases and 9018 controls, Lys/Gln genotype and overall cancer with OR=0.99 (95% CI, 0.92-1.06), Gln/Gln genotype OR=1.16 (95% CI, 1.05-1.28); the stratified analysis, the genotype of Gln and Gln/ patients with OR=1.28 (95% CI, 1.07-1.53), in the Asian population and OR=1.21 combination (95% CI, 1.03-1.43). (2) Ala~ (499) Val gene polymorphism, 10 of a total of 5581 cases and 6351 controls, with overall cancer OR values were: Ala/Val genotype OR=0.94 (95% CI (0.84-1.06), random effects model), Val/Val genotype OR=1.24 (95% CI, 1.08-1.42) (fixed effect model); hierarchical analysis, Val/Val genotype and bladder cancer with OR=1.33 (95% CI, 1.06-1.68), in Caucasians, with OR=1.41 (95% CI, 1.16-1.71). (3) PAT-/+ gene polymorphism is 16 A Study of 4514 cases and 5538 Controls, PAT+/- genotype OR = 0.98 (95% CI, 0.90-1.07), PAT+/+ genotype OR = 1.03 (95% CI, 0.91-1.16). (4) gene smoking interaction analysis showed that in non-smokers, risk of carrying PAT+/+ genotype increased cancer (OR = 1.44,95%CI 1.02-2.05; Q test P = 0.766), and the PAT-/+ genotype of non-smokers cancer risk no significant increase (OR = 0.99,95% CI 0.77-1.26).
2. path analysis results showed that the coke oven exposure and smoking are important factors for the urinary concentration of 1-OHP, the model decision coefficient is 0.75; factors have significant influence on the size from the comet tail is: the concentration of urinary 1-OHP XRCC1-exon9 variant genotype ERCC2-exon10 genotype XRCC1-exon6 genotype, 0.22 factors model decision coefficient; the role and size have a significant impact on the CBMN micronucleus rate: exposure of coke oven urine 1-OHP concentration age mEH3 variant genotype ERCC2-exon10 genotype XRCC1-exon6 genotype, the determination coefficient of the model was 0.27.
The structure of BP neural network constructed by the 3. 17-8-1, the influence factors of micronucleus MIV value for coke oven exposure (0.0011) and the other, relatively large impact factors, mEH3 genotype, ERCC2-exon10 genotype, XRCC1-exon10 genotype, smoking, the mEH3 genotype plays a negative role on the micronucleus.
Conclusion: good quality meta analysis can make up the defect sample molecular epidemiology analysis shortage brought to a certain extent, concluded that.XPC gene polymorphism certainly has weak role in tumorigenesis, and there is interaction between gene and smoking for exogenous factors, especially in coke oven exposure the early genetic damage plays an important role, which is greater than the genotype. The path analysis and the neural network model can serve as risk factors for disease screening in epidemiology.

【学位授予单位】：华中科技大学
【学位级别】：硕士
【学位授予年份】：2008
【分类号】：R363

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