【作者】 张娟；

【导师】 浦跃朴；

【作者基本信息】 东南大学 ， 劳动卫生与环境卫生学， 2004， 硕士

【摘要】 白血病是我国十大高发恶性肿瘤之一,它的病因及发病机理至今未完全清楚,目前认为是多种环境与遗传因素互相作用的结果。本课题旨在研究我国汉族人群成人急性白血病的环境危险因素和遗传易感性,环境-基因的交互作用及其与白血病发生的关系。本文分三个部分进行阐述:1. 成人急性白血病环境危险因素的流行病学研究 应用1:1配对病例-对照流行病学调查方法,对来自江苏汉族人群的原发性成人急性白血病和对照各135例从用药史、居住环境周围三废污染、职业史、居室装潢史、吸烟史、染发史等14项可能危险因素进行调查,应用单因素与多因素条件logistic回归模型结合的统计分析方法,在α=0.05的水平上,筛选出居住环境周围三废污染(OR:4.499,95%CI:1.856～10.905)、职业接触有机溶剂(OR:2.564,95%CI:1.028～6.391)、装潢后入住间隔(OR:1.672 ,95%CI:1.170～2.390)、染发年限(OR:1.679 ,95%CI:1.044～2.699)等4项因素为成人急性白血病的环境危险因素,综合归因危险度为0.5502。其中装潢后三个月内入住者,患成人急性白血病的相对危险度是装潢后三个月以上入住者的1.672倍;连续染发5年以上患成人急性白血病的相对危险度是染发5年以内者的1.679倍。将结果按病理类型分析统计,筛检出居住环境周围三废污染、职业接触有机溶剂、染发年限等3项因素为急性髓性白血病的环境危险因素,其综合归因危险度为0.4201,且连续染发5年以上者患成人急性髓性白血病的相对危险度是染发5年以内的1.830倍。装潢后入住间隔为急性淋巴细胞性白<WP=7>血病的环境危险因素,其归因危险度为0.2970。2.基因多态性和成人急性白血病易感性关系的研究应用PCR-RFLP技术,检测与分析病例与对照的CYP1A1、GSTT1、GSTM1、NQO1、P2X7、XRCC1、XPD基因多态性分布。结果表明中国江苏汉族人群中,CYP1A16235T,NQO1609T,P2X71513C,XRCC1399Gln,XPD751Gln等位基因频率分别为32.7%,34.4%,9.1%,25.8%,10.8%。CYP1A16235 C/C,C/T,T/T 基因型频率分别为49.5%,37.6%,13.9%;GSTT1、GSTM1缺失基因型频率为38.6%,33.3%;NQO1609 C/C,C/T,T/T基因型频率分别为44.5%,42.4%,13.1%;P2X71513 A/A,A/C,C/C基因型频率分别为82.8%,16.2 %,1.0%;XRCC1399 Arg/ Arg,Arg/ Gln,Gln/ Gln基因型频率分别为55.6%,37.4%,7.0%;XPD751Lys/Lys,Lys/Gln,Gln/Gln基因型频率分别为81.4%,15.7%,2.9%。应用X2检验筛检出CYP1A1、GSTT1、P2X7、XPD基因是成人急性白血病的易感基因,携带CYP1A1 6235T (OR:3.1957 ,95%CI:1.7417～5.8642), GSTT1缺失型 (OR:1.9008 ,95%CI:1.0855～3.3283), P2X7 1513C, (OR:1.9983 ,95%CI:1.0141～3.9379)、XPD751Gln (OR:2.1842 ,95%CI:1.1443～4.1693) 突变等位基因者,患急性白血病的危险性增加。将结果按病理类型进行分析统计,CYP1A1是急性髓性白血病、CYP1A1与XPD是急性淋巴细胞性白血病的易感基因。基因-基因交互作用分析结果显示同时携带CYP1A16235T与 XRCC1399Gln突变基因型或P2X71513C与XRCC1399Gln突变基因型对急性白血病的发生存在协同作用,同时携带两种突变基因型者患急性白血病的危险性比单独携带其中任何一个突变基因型明显增加。3.环境危险因素与基因多态性在成人急性白血病发生中的交互作用研究应用非条件Logistic多元回归模型分析环境-基因的交互作用,在α=0.05的水平上得出职业接触有机溶剂与CYP1A16235T突变基因型(OR:14.868 P=0.0304),染发史与CYP1A16235T突变基因型(OR:12.369,P=0.0002,),居室装潢污染与XPD751Gln突变基因型 (OR:3.793,P= 0.0404) 分别在成人<WP=8>急性白血病的发生中有协同作用。同时携带CYP1A16235T与 NQO1609T双突变基因型者暴露居住环境周围三废污染,患急性白血病的危险性比单独携带其中任何一个突变基因型明显增加。在急性髓性白血病的发生中,染发史与CYP1A16235T突变基因型有协同作用。综合以上内容,可获得以下主要结论:1.暴露于居住环境周围三废污染,职业接触有机溶剂,装潢后入住间隔,染发年限等是成人急性白血病发生的环境危险因素;居住环境周围三废污染、职业接触有机溶剂、染发年限等为急性髓性白血病的环境危险因素;装潢后入住间隔为急性淋巴细胞性白血病的环境危险因素。2.CYP1A1、GSTT1、P2X7、XPD基因是成人急性白血病的易感基因,其易感基因型分别为CYP1A1 6235T突变型、GSTT1缺失型、P2X7 1513 C突变型和XPD751Gln突变型。其中CYP1A1是急性髓性白血病和急性淋巴细胞性白血病的易感基因。同时携带CYP1A16235T与 XRCC1399Gln突变基因型,或P2X71513C与XRCC1399Gn突变基因型在急性白血病的发生中存在协同作用。3.在成人急性白血病发生中,职业接触有机溶剂与携带CYP1A16235T突变基因型、染发史与携带CYP1A16235T突变基因型、居室装潢污染与携带XPD751Gln突变基因型分别有协同作用。同时携带CYP1A16235T与 NQO1609T双突变基因型者暴露周围环境三废污染,患急性白血病的危险性比单独携带其中任何一个突变基因型明显增加。4.居室装潢和染发是成人急性白血病的危险因素。装潢后3个月内入住、或使用氧化型染发剂连续染发5年以上可明显增加患急性白血病的危险性。装潢后过早入住主要与急性淋?更多还原

【Abstract】 Environmental and genetic factors are commonly considered to jointly result in cancers. A matched case-control study has been carried out to explore the possible relationship between environmental risk factors, genetic polymorphisms of metabolic enzyme, receptor, DNA repair genes and adult acute leukemia in Chinese Han population. The polymorphisms of the genes were genotyped by PCR-RFLP analysis. Conditional logistic regression model was applied to screen 14 possible environmental risk factors and to analyze the interaction between environmental risk factors and genetic polymorphisms to adult acute leukemia. The principle results were as follows: Epidemiology study on environmental risk factors to adult acute leukemia. A paired case-control study was performed to screen the 14 possible risk factors such as pollution around the inhabitancy, oral history of chloromycetin, exposure history of x-ray, exposure history of organic solvents, history of hair dye use, house decoration history in 135 cases and 135 controls from Chinese Han population of Jiangsu province. According to the preceding data on epidemiology, the results show pollution around the inhabitancy (OR:4.499,95%CI: 1.856～10.905), occupational exposure history of organic solvents (OR:2.564,95%CI:1.028～6.391), the moving interval after house decoration (OR:1.672,95%CI:1.170～2.390), the years of oxidant hair dye use (OR:1.679,95%CI:1.044～2.699) were four of the environmental risk factors to adult acute leukemia analyzed by conditional multiple regression model <WP=10>(α=0.05). Summary population attribute risk (PAR) of the above four was 0.5502. The risk of the moving interval after house decoration in three months was 1.672 times of that over three months. The risk of the oxidant hair dye use over five years was 1.679 times of that in five years. Further analysis showed pollution around the inhabitancy, occupational exposure history of organic solvents, the years of oxidant hair dye use were the environmental risk factors of acute myelocytic leukemia (AML) and the Summary PAR was 0.4201. The risk of the oxidant hair dye use over five years was 1.830 times of that in five years. The risk factor of acute lymphocytic leukemia (ALL) was the moving interval after house decoration and its adjusted PAR was 0.2970. 2. The relationship between the polymorphism of genes and susceptibility to adult acute leukemiaThe genetic polymorphisms of 7 metabolic enzyme, receptor and DNA repair genes of CYP1A1, GSTT1, GSTM1, NQO1, P2X7 A1513C, XRCC1, XPD were genotyped by PCR-RFLP analysis in peripheral blood DNA samples from both cases and controls. The normal genotypes frequency of CYP1A16235 C/C,C/T,T/T were 49.5%,37.6%,13.9%; GSTT1-、GSTM1- were 38.6%,33.3%; NQO1609 C/C,C/T,T/T were 44.5%,42.4%,13.1%; P2X71513 A/A,A/C,C/C were 82.8%, 16.2 %, 1.0%; XRCC1399 Arg/ Arg,Arg/ Gln,Gln/ Gln were 55.6%, 37.4%, 7.0%; XPD751Lys/Lys,Lys/Gln,Gln/Gln were 81.4%,15.7%,2.9%. CYP1A1, GSTT1, P2X7, XPD were susceptible genes of adult acute leukemia and the susceptible genotypes were CYP1A1 6235C/T ,T/T; GSTT1(-), P2X7 1513C/A,C/C; XPD 751 Lys /Gln, Gln/Gln, respectively. The CYP1A1 was susceptible gene for AML, The CYP1A1 and XPD were susceptible genes for ALL. The interaction between CYP1A16235 and XRCC1399 mutant genotypes was found to have synergistic effect to the occurrence of acute leukemia which provided the evidence of significantly higher susceptibility to acute leukemia in individuals with two mutant genotypes of CYP1A16235 and XRCC1399 than with only one of the two mutant genotype , So was P2X71513 and XRCC1399. <WP=11>3. The interaction between environmental risk factors and genetic polymorphisms in the occurrence of adult acute leukemia The interaction between environmental risk factors and genetic polymorphisms was analyzed by unconditional multiple logistic regression model. The significant interactions of synergistic effect between CYP1A16235 mutant genotype and occupational exposure history of organic solvents (OR=16.868, P=0.0304) or oxidant hai更多还原