铁矿工矽肺的遗传易感性研究
|
摘要
矽肺是我国最为严重的职业卫生问题之一，患病人数多，病死率高。有证据表明矽肺的发生由多种因素决定，如SiO_2粉尘暴露和个体易感性等，而个体易感性又部分地取决于遗传易感性。矽肺的发生机制相当复杂，至今尚未明确，可能涉及：矽尘诱导肺泡巨噬细胞(alveolar macrophages，AMs)释放大量炎症纤维化因子、激活信号转导通路以及由矽尘产生的活性氧族(ROS)／活性氮族(RNS)诱导的细胞凋亡，最终引起肺成纤维细胞增殖及细胞外基质的沉积。目前有关矽肺遗传易感性的研究较少，本课题主婴探讨细胞因子、转录因子以及凋亡分子基因多态与铁矿工矽肺遗传易感性的关系，分析“职业暴露-生活方式-遗传易感性”的联合作用对个体矽肺发病风险的影响。
本课题主要包括职业流行病学调查和矽肺遗传易感性研究两方面的内容。研究对象为295例来自安徽省某铁矿的汉族男性接尘工人。我们通过收集现场粉尘浓度资料估算工人既往累积总粉尘接触量，通过问卷调查获得研究对象的一般情况以及健康状况；通过收集健康监护资料了解矿工肺结核患病情况，并对所有研究对象进行肺功能测试评估矿工呼吸功能受损情况。采用病例-对照设计，以职业病防治机构确诊的184例矽肺病人为病例组，年龄、接尘工龄相近而无矽肺的111例接尘矿工为对照组，应用聚合酶链反应(polymerase chain reaction，PCR)-限制性片段长度多态性(restriction fragment length polymorphism，RFLP)和创造酶切位点的限制性片段长度多态性(create restriction site combined with restriction fragment length polymorphism，CRS-RFLP)检测技术，我们分析了细胞因子(TNF-α、TNF-β、IL-1α、IL—1β、IL-1RA、TGF-β1、IL-10和IFN-γ)、信号分子(NF-κB和IκB)以及凋亡分子(FAS和FASL)基因的多态性。
以累积总粉尘接触量(cumulative total dust exposure，CTE)为指标，对所有研究对象进行粉尘暴露评估。病例组平均CTE显著高于对照组(242.6±98.8mg·a／m~3vs 217.6±100.7mg·a／m~3)，其中Ⅰ期矽肺组(111例)平均CTE为229.4±102.3mg·a／m~3，Ⅱ期矽肺组(62例)为262.9±91.3mg·a／m~3，Ⅲ期矽肺组(11例)为260.4±88.9mg·a／m~3。在矽肺的遗传易感性研究中，病例组和对照组暴露水平的差异将通过统计学方法加以校正。分析时将连续型变量转换为等级分类变量，即低暴露组(CTE＜150mg·a／m~3)、中暴露组(CTE≥150mg·a／m~3)和高暴露组(CTE≥300mg·a／m~3)三组。
粉尘暴露及矽肺患病对矿工健康状况影响的研究表明：(1)矽肺的临床表现主要包括：矽肺相关症状，如胸闷(92.9％)、慢性咳嗽(73.9％)、咳粘液痰(62.5％)；肺结核相关症状，如痰中带血(30.4％)、持续性低热(24.5％)、近期体重减轻(28.8％)；呼吸困难(97.3％)。其中，呼吸困难程度随矽肺晋级及累积总粉尘接触量增加而加重。在非矽肺矿工中，相当比例的人有身体不适反应。(2)矽肺组肺结核患病率为27.2％，对照组肺结核患病率为9.9％，矽肺组患肺结核的危险性是对照组的6.09倍。肺结核患病率随矽肺晋级及累积总粉尘接触量增加而升高。(3)矿工肺功能异常的主要类型为限制性和混合性通气功能障碍。Ⅲ期矽肺肺功能障碍率为100.0％、Ⅱ期矽肺86.4％、Ⅰ期矽肺76.4％、对照组45.4％。随累积总粉尘暴露量增加肺功能正常率降低、肺功能障碍率升高。
铁矿工矽肺的遗传易感性研究结果表明：(1)TNF-α-308 G＞A、TNF-α-238G＞A、IL-1α-889 C＞T、IL-1β+3953 C＞T和IL-10-1082 A＞G四个位点突变率比较低，突变纯合型很少(分别为5、1、5、1和4例)。IL-1RA VNTR~*2／~*2型也仅有1例。检出TGF-β+915 G＞C多态位点突变杂合子(G／C)仅2例(均为矽肺患者)，未检出突变纯合子(C／C)。各位点基因多态在矽肺发病的遗传易感性中不起主要作用，但TNF-α-308多态性与吸烟有交互作用，携带A等位基因的吸烟工人比携带G／G基因型的吸烟工人更易发生矽肺(OR=2.41，95％CI：1.13～5.13)；双体型分析结果表明，IL-1多态位点3／3双体型的携带者矽肺患病率是1／1双体型携带者的5.17倍(OR=5.17，95％CI：1.41～18.88，P=0.008)；IL-10多态位点1／3双体型的携带者矽肺患病率是1／1双体型携带者的13.91倍(OR=13.91，95％CI：1.82～106.29，P=0.001)。(2)NFKB1-94ins／delATTG ins／del基因型在病例组和对照组间的分布频率分别为42.6％和52.3％，无显著性差异，校正累积总粉尘接触量和吸烟后，χ~2检验显示两组间的分布存在显著性差异(ORadj=0.57，95％CI：0.32～0.998，P=0.047)，表明携带ins／del基因型的个体较携带ins／ins基因型的个体发生矽肺的危险性降低；按期别分层后，Ⅰ期矽肺和Ⅱ+Ⅲ期矽肺中ins／del+del／del基因型频率均低于对照组(分别为68.2％vs 74.8％和58.9％vs74.8％)，等级相关分析有统计学意义(spearman相关系数-0.13)，提示NFKB1-94ins／delATTG多态可能与矽肺的严重程度也密切相关。(3)FAS-1377 A／A基因型在病例组和对照组间的分布频率分别为9.3％和18.0％，无显著性差异，校正累积总粉尘接触量和吸烟后，χ~2检验显示两组间的分布存在显著性差异(ORadi=0.42，95％CI：0.19～0.93，P=0.029)，表明携带A／A基因型的个体较携带G／G基因型的个体发生矽肺的危险性降低；FAS基因单倍型分析结果表明，病例组携带单倍型-1377G／-670G的比例显著高于对照组(9.6％vs 3.6％)，这种单倍型的携带者矽肺患病率是单倍型-1377G／-670A携带者的2.71倍(OR=2.71，95％CI：1.22～6.03，P=0.01)。
综上，建议预防矿工矽肺应主要通过控制作业场所粉尘浓度，同时做好个体防护，减少粉尘暴露；完善健康监护制度，加强作业场所戒烟宣传和健康教育；识别易感人群(如NFKB1-94ins／delATTG ins／del基因型和FAS-1377 A／A基因型携带者等)。最终降低矽肺的发病率，保障矿工健康、提高矽肺病人生命质量。
Silicosis has been one of the most serious occupational health problems in China,with high morbidity and mortality. Cumulative dust exposure is the most importantfactor in the pathogenesis of silicosis, however, there appears to be quite pronouncedindividual variation in silicosis susceptibility and severity, suggesting that geneticfactors may influence progression of the disease. Although the exact mechanismsleading to silicosis have to be elucidated, recent in vivo, in vitro, and human studieshave focused on increased expression of inflammatory and fibrogenic cytokines, suchas tumor necrosis factor-alpha(TNF-α) and interleukin(IL)-1, activation of specifictranscription factors(e.g., nuclear factor kappa B(NF-kB) and AP-1) and apoptosis inmacrophages and other cells induced by the ROS, RNS, and NO generated by thesilica particles. Few studies have investigated genetic susceptibility to silicosis andthis study was to investigate the roles of genetic polymorphisms in cytokines,transcriptional factors, and apoptosis molecules in susceptibility to silicosis and toexplore the interactions of environmental factors(occupational exposure and lifestyles) and genetic factors(genetic polymorphisms) in risk of silicosis in Chinese ironminers.
Enrolled in the study were 295 retired male miners from an iron mine in AnhuiProvince, China. Cumulative total dust exposure(CTE) was assesed based on thehistorical record of total airborne dust concentration in various work locations; astandardized questionnaire was used to obtain general characteristics and health statusof all participants; health surveillance data was collected to obtain the prevalence ofpulmonary tuberculosis(PTB), and pulmonary function test was conducted in allparticipants to assess pulmonary function damage of miners. A case-control study wasconducted with 183 silicosis patients and 111 silica-exposed miners who werefrequency-matched by age, dust exposure duration, work location, and type of work.Genotype analysis was performed on genomic DNA, using a polymerase chainreaction-restrained fragment length polymorphism(PCR-RFLP) assay.
The occupational exposure level of each subject was assessed by cumulative totaldust exposure(CTE). Despite the recruitment of high dust exposure miners in thecontrols, the mean CTE among silicosis patients was still significantly higher than thatin the controls(242.6±98.8 mg·a/m~3 vs 217.6±100.7 mg·a/m~3, P＜0.05). The average CTE was 229.4±102.3 mg·a/m~3 in stageⅠgroup, 262.9±91.3 mg·a/m~3 in stageⅡgroup,and 260.4±88.9 mg·a/m~3 in stageⅢgroup. In further study for genetic susceptibilityto silicosis, based on the distribution of CTE, three levels of exposure were defined:＜150 mg·a/m~3(low exposure),≥150-mg·a/m~3(moderate exposure), and≥300mg·a/m~3(high exposure).
The study on health effects caused by silica exposure and silicosis indicated: (1)Clinical manifestations of silicosis included: silicosis-related symptoms, such as cheststuffiness(92.9%), chronic cough(73.9%), and phlegm production(62.5%);PTB-related symptoms, such as bloody phlegm(30.4%), persistent hypothermia(24.5%), and current body weight loss(28.8%); dyspnea. Severity of dyspneaincreased with silicosis upgrading and CTE increase, and there was an 8.85-foldincrease risk of dyspnea for silicosis cases compared with controls. Furthermore, asizeable proportion of controls had respiratory symptoms. (2) The prevalence of PTBwas 27.2% in cases and 9.9% in controls. There was a 6.09-fold increased risk of PTBfor silicosis cases compared with controls. The prevalence of PTB increased withsilicosis upgrading and CTE increase. (3) The main types of pulmonary dysfunctionwere restrictive and mixed hypoventilation. Prevalence of pulmonary dysfunctionincreased with silicosis upgrading, which was 45.5% in control, 76.4% in stageⅠgroup, 86.4% in stageⅡgroup, and 100.0% in stageⅢgroup, respectively. The sametrend was found between prevalence of pulmonary dysfunction and gruops of CTE.
The study on genetic susceptibility to silicosis in iron miners indicated: (1) Thefrequencies of the variant allele for polymorphisms of TNF-α-308 G＞A, TNF-α-238G＞A, IL-1α-889 C＞T, IL-1β+3953 C＞T and IL-10-1082 A＞G were low, with varianthomozygote of 5, 1, 5, 1, and 4 cases, respectively. There was only one case carryingIL-1RA VNTR *2/*2 genotype. We detected only two silicosis patients with GCheterozygote for TGF-β1+915 G＞C polymorphism, and no variant homozygote CCwas detected. No association was observed between all the cytokine polymorphismsand silicosis, however, the TNF-α-308 G＞A variant had synergistic effect withsmoking, and smoking miners with A allele were more susceptible to silicosis thanindividuals carrying homozygote G/G(OR=2.41, 95%CI: 1.13～5.13). Diplotypeanalysis showed that risk of silicosis increased in the subjects with the 3/3 diplotypecompared with those carrying the 1/1 diplotype of IL-1 gene(OR=5.17, 95%CI:1.41～18.88, P=0.008); in the subjects with 1/3 diplotype compared with those withthe 1/1 diplotype of IL-10 gene(OR=13.91, 95%CI: 1.82～106.29, P=0.001). (2) The distribution of the NFKB1-94ins/delATTG ins/del genotype was similar between casesand controls(42.6% and 52.3%, respectively), when CTE and smoking were includedin the analysis as covariates, the risk of silicosis for individuals with the ins/delgenotype was 0.57-fold(ORadj=0.57, 95%CI: 0.32～0.998, P=0.047) compared withthose with the ins/ins genotype. Stratified by the grades of silicosis, the frequencies ofins/del+del/del genotypes in cases of stageⅡand stageⅢ, and stageⅠwere lowerthan that in the controls(68.2% vs 74.8% and 58.9% vs 74.8%, respectively); rankcorrelation analysis showed a statistically significant correlation between theNFKB1-94ins/delATTG variant and silicosis severity(spearman correlationcoefficient-0.13). (3) The distribution of the FAS-1377 A/A genotype was similarbetween cases and controls(9.3% and 18.0%, respectively), when CTE and smokingwere included in the analysis as covariates, the risk of silicosis for subjects with theA/A genotype was 0.42-fold(ORadj=0.42, 95%CI: 0.19～0.93, P=0.029) comparedwith those with the G/G genotype. Haplotype analysis showed that there was astatistically significant difference for the distribution of HAP2 haplotype[(-1377Gand -670G), P=0.007] between cases and controls. Compared with those carrying theHAP1 haplotype(-1377G and -670A), there was a 2.71-fold increased risk of silicosisfor subjects with the HAP2 haplotype(OR=2.71, 95%CI: 1.22～6.03, P=0.01).
In conclusion, it suggested that comprehensive measures should be applied toprevent silicosis, including dust control at workplace, application of personalprotective equipment(PPE), health surveillance, smoking cessation propaganda andhealth education, and screening the susceptible workers(e.g. individuals withNFKB1-94ins/delATTG ins/del and FAS-1377 A/A genotypes), which would becombined to reduce incidence of silicosis and to improve life quality of workers.
本课题主要包括职业流行病学调查和矽肺遗传易感性研究两方面的内容。研究对象为295例来自安徽省某铁矿的汉族男性接尘工人。我们通过收集现场粉尘浓度资料估算工人既往累积总粉尘接触量，通过问卷调查获得研究对象的一般情况以及健康状况；通过收集健康监护资料了解矿工肺结核患病情况，并对所有研究对象进行肺功能测试评估矿工呼吸功能受损情况。采用病例-对照设计，以职业病防治机构确诊的184例矽肺病人为病例组，年龄、接尘工龄相近而无矽肺的111例接尘矿工为对照组，应用聚合酶链反应(polymerase chain reaction，PCR)-限制性片段长度多态性(restriction fragment length polymorphism，RFLP)和创造酶切位点的限制性片段长度多态性(create restriction site combined with restriction fragment length polymorphism，CRS-RFLP)检测技术，我们分析了细胞因子(TNF-α、TNF-β、IL-1α、IL—1β、IL-1RA、TGF-β1、IL-10和IFN-γ)、信号分子(NF-κB和IκB)以及凋亡分子(FAS和FASL)基因的多态性。
以累积总粉尘接触量(cumulative total dust exposure，CTE)为指标，对所有研究对象进行粉尘暴露评估。病例组平均CTE显著高于对照组(242.6±98.8mg·a／m~3vs 217.6±100.7mg·a／m~3)，其中Ⅰ期矽肺组(111例)平均CTE为229.4±102.3mg·a／m~3，Ⅱ期矽肺组(62例)为262.9±91.3mg·a／m~3，Ⅲ期矽肺组(11例)为260.4±88.9mg·a／m~3。在矽肺的遗传易感性研究中，病例组和对照组暴露水平的差异将通过统计学方法加以校正。分析时将连续型变量转换为等级分类变量，即低暴露组(CTE＜150mg·a／m~3)、中暴露组(CTE≥150mg·a／m~3)和高暴露组(CTE≥300mg·a／m~3)三组。
粉尘暴露及矽肺患病对矿工健康状况影响的研究表明：(1)矽肺的临床表现主要包括：矽肺相关症状，如胸闷(92.9％)、慢性咳嗽(73.9％)、咳粘液痰(62.5％)；肺结核相关症状，如痰中带血(30.4％)、持续性低热(24.5％)、近期体重减轻(28.8％)；呼吸困难(97.3％)。其中，呼吸困难程度随矽肺晋级及累积总粉尘接触量增加而加重。在非矽肺矿工中，相当比例的人有身体不适反应。(2)矽肺组肺结核患病率为27.2％，对照组肺结核患病率为9.9％，矽肺组患肺结核的危险性是对照组的6.09倍。肺结核患病率随矽肺晋级及累积总粉尘接触量增加而升高。(3)矿工肺功能异常的主要类型为限制性和混合性通气功能障碍。Ⅲ期矽肺肺功能障碍率为100.0％、Ⅱ期矽肺86.4％、Ⅰ期矽肺76.4％、对照组45.4％。随累积总粉尘暴露量增加肺功能正常率降低、肺功能障碍率升高。
铁矿工矽肺的遗传易感性研究结果表明：(1)TNF-α-308 G＞A、TNF-α-238G＞A、IL-1α-889 C＞T、IL-1β+3953 C＞T和IL-10-1082 A＞G四个位点突变率比较低，突变纯合型很少(分别为5、1、5、1和4例)。IL-1RA VNTR~*2／~*2型也仅有1例。检出TGF-β+915 G＞C多态位点突变杂合子(G／C)仅2例(均为矽肺患者)，未检出突变纯合子(C／C)。各位点基因多态在矽肺发病的遗传易感性中不起主要作用，但TNF-α-308多态性与吸烟有交互作用，携带A等位基因的吸烟工人比携带G／G基因型的吸烟工人更易发生矽肺(OR=2.41，95％CI：1.13～5.13)；双体型分析结果表明，IL-1多态位点3／3双体型的携带者矽肺患病率是1／1双体型携带者的5.17倍(OR=5.17，95％CI：1.41～18.88，P=0.008)；IL-10多态位点1／3双体型的携带者矽肺患病率是1／1双体型携带者的13.91倍(OR=13.91，95％CI：1.82～106.29，P=0.001)。(2)NFKB1-94ins／delATTG ins／del基因型在病例组和对照组间的分布频率分别为42.6％和52.3％，无显著性差异，校正累积总粉尘接触量和吸烟后，χ~2检验显示两组间的分布存在显著性差异(ORadj=0.57，95％CI：0.32～0.998，P=0.047)，表明携带ins／del基因型的个体较携带ins／ins基因型的个体发生矽肺的危险性降低；按期别分层后，Ⅰ期矽肺和Ⅱ+Ⅲ期矽肺中ins／del+del／del基因型频率均低于对照组(分别为68.2％vs 74.8％和58.9％vs74.8％)，等级相关分析有统计学意义(spearman相关系数-0.13)，提示NFKB1-94ins／delATTG多态可能与矽肺的严重程度也密切相关。(3)FAS-1377 A／A基因型在病例组和对照组间的分布频率分别为9.3％和18.0％，无显著性差异，校正累积总粉尘接触量和吸烟后，χ~2检验显示两组间的分布存在显著性差异(ORadi=0.42，95％CI：0.19～0.93，P=0.029)，表明携带A／A基因型的个体较携带G／G基因型的个体发生矽肺的危险性降低；FAS基因单倍型分析结果表明，病例组携带单倍型-1377G／-670G的比例显著高于对照组(9.6％vs 3.6％)，这种单倍型的携带者矽肺患病率是单倍型-1377G／-670A携带者的2.71倍(OR=2.71，95％CI：1.22～6.03，P=0.01)。
综上，建议预防矿工矽肺应主要通过控制作业场所粉尘浓度，同时做好个体防护，减少粉尘暴露；完善健康监护制度，加强作业场所戒烟宣传和健康教育；识别易感人群(如NFKB1-94ins／delATTG ins／del基因型和FAS-1377 A／A基因型携带者等)。最终降低矽肺的发病率，保障矿工健康、提高矽肺病人生命质量。
Silicosis has been one of the most serious occupational health problems in China,with high morbidity and mortality. Cumulative dust exposure is the most importantfactor in the pathogenesis of silicosis, however, there appears to be quite pronouncedindividual variation in silicosis susceptibility and severity, suggesting that geneticfactors may influence progression of the disease. Although the exact mechanismsleading to silicosis have to be elucidated, recent in vivo, in vitro, and human studieshave focused on increased expression of inflammatory and fibrogenic cytokines, suchas tumor necrosis factor-alpha(TNF-α) and interleukin(IL)-1, activation of specifictranscription factors(e.g., nuclear factor kappa B(NF-kB) and AP-1) and apoptosis inmacrophages and other cells induced by the ROS, RNS, and NO generated by thesilica particles. Few studies have investigated genetic susceptibility to silicosis andthis study was to investigate the roles of genetic polymorphisms in cytokines,transcriptional factors, and apoptosis molecules in susceptibility to silicosis and toexplore the interactions of environmental factors(occupational exposure and lifestyles) and genetic factors(genetic polymorphisms) in risk of silicosis in Chinese ironminers.
Enrolled in the study were 295 retired male miners from an iron mine in AnhuiProvince, China. Cumulative total dust exposure(CTE) was assesed based on thehistorical record of total airborne dust concentration in various work locations; astandardized questionnaire was used to obtain general characteristics and health statusof all participants; health surveillance data was collected to obtain the prevalence ofpulmonary tuberculosis(PTB), and pulmonary function test was conducted in allparticipants to assess pulmonary function damage of miners. A case-control study wasconducted with 183 silicosis patients and 111 silica-exposed miners who werefrequency-matched by age, dust exposure duration, work location, and type of work.Genotype analysis was performed on genomic DNA, using a polymerase chainreaction-restrained fragment length polymorphism(PCR-RFLP) assay.
The occupational exposure level of each subject was assessed by cumulative totaldust exposure(CTE). Despite the recruitment of high dust exposure miners in thecontrols, the mean CTE among silicosis patients was still significantly higher than thatin the controls(242.6±98.8 mg·a/m~3 vs 217.6±100.7 mg·a/m~3, P＜0.05). The average CTE was 229.4±102.3 mg·a/m~3 in stageⅠgroup, 262.9±91.3 mg·a/m~3 in stageⅡgroup,and 260.4±88.9 mg·a/m~3 in stageⅢgroup. In further study for genetic susceptibilityto silicosis, based on the distribution of CTE, three levels of exposure were defined:＜150 mg·a/m~3(low exposure),≥150-mg·a/m~3(moderate exposure), and≥300mg·a/m~3(high exposure).
The study on health effects caused by silica exposure and silicosis indicated: (1)Clinical manifestations of silicosis included: silicosis-related symptoms, such as cheststuffiness(92.9%), chronic cough(73.9%), and phlegm production(62.5%);PTB-related symptoms, such as bloody phlegm(30.4%), persistent hypothermia(24.5%), and current body weight loss(28.8%); dyspnea. Severity of dyspneaincreased with silicosis upgrading and CTE increase, and there was an 8.85-foldincrease risk of dyspnea for silicosis cases compared with controls. Furthermore, asizeable proportion of controls had respiratory symptoms. (2) The prevalence of PTBwas 27.2% in cases and 9.9% in controls. There was a 6.09-fold increased risk of PTBfor silicosis cases compared with controls. The prevalence of PTB increased withsilicosis upgrading and CTE increase. (3) The main types of pulmonary dysfunctionwere restrictive and mixed hypoventilation. Prevalence of pulmonary dysfunctionincreased with silicosis upgrading, which was 45.5% in control, 76.4% in stageⅠgroup, 86.4% in stageⅡgroup, and 100.0% in stageⅢgroup, respectively. The sametrend was found between prevalence of pulmonary dysfunction and gruops of CTE.
The study on genetic susceptibility to silicosis in iron miners indicated: (1) Thefrequencies of the variant allele for polymorphisms of TNF-α-308 G＞A, TNF-α-238G＞A, IL-1α-889 C＞T, IL-1β+3953 C＞T and IL-10-1082 A＞G were low, with varianthomozygote of 5, 1, 5, 1, and 4 cases, respectively. There was only one case carryingIL-1RA VNTR *2/*2 genotype. We detected only two silicosis patients with GCheterozygote for TGF-β1+915 G＞C polymorphism, and no variant homozygote CCwas detected. No association was observed between all the cytokine polymorphismsand silicosis, however, the TNF-α-308 G＞A variant had synergistic effect withsmoking, and smoking miners with A allele were more susceptible to silicosis thanindividuals carrying homozygote G/G(OR=2.41, 95%CI: 1.13～5.13). Diplotypeanalysis showed that risk of silicosis increased in the subjects with the 3/3 diplotypecompared with those carrying the 1/1 diplotype of IL-1 gene(OR=5.17, 95%CI:1.41～18.88, P=0.008); in the subjects with 1/3 diplotype compared with those withthe 1/1 diplotype of IL-10 gene(OR=13.91, 95%CI: 1.82～106.29, P=0.001). (2) The distribution of the NFKB1-94ins/delATTG ins/del genotype was similar between casesand controls(42.6% and 52.3%, respectively), when CTE and smoking were includedin the analysis as covariates, the risk of silicosis for individuals with the ins/delgenotype was 0.57-fold(ORadj=0.57, 95%CI: 0.32～0.998, P=0.047) compared withthose with the ins/ins genotype. Stratified by the grades of silicosis, the frequencies ofins/del+del/del genotypes in cases of stageⅡand stageⅢ, and stageⅠwere lowerthan that in the controls(68.2% vs 74.8% and 58.9% vs 74.8%, respectively); rankcorrelation analysis showed a statistically significant correlation between theNFKB1-94ins/delATTG variant and silicosis severity(spearman correlationcoefficient-0.13). (3) The distribution of the FAS-1377 A/A genotype was similarbetween cases and controls(9.3% and 18.0%, respectively), when CTE and smokingwere included in the analysis as covariates, the risk of silicosis for subjects with theA/A genotype was 0.42-fold(ORadj=0.42, 95%CI: 0.19～0.93, P=0.029) comparedwith those with the G/G genotype. Haplotype analysis showed that there was astatistically significant difference for the distribution of HAP2 haplotype[(-1377Gand -670G), P=0.007] between cases and controls. Compared with those carrying theHAP1 haplotype(-1377G and -670A), there was a 2.71-fold increased risk of silicosisfor subjects with the HAP2 haplotype(OR=2.71, 95%CI: 1.22～6.03, P=0.01).
In conclusion, it suggested that comprehensive measures should be applied toprevent silicosis, including dust control at workplace, application of personalprotective equipment(PPE), health surveillance, smoking cessation propaganda andhealth education, and screening the susceptible workers(e.g. individuals withNFKB1-94ins/delATTG ins/del and FAS-1377 A/A genotypes), which would becombined to reduce incidence of silicosis and to improve life quality of workers.
引文
[1] 金泰廙，孙贵范．职业卫生与职业医学[J]．2003：77-79．
[2] Calvert G M,Rice F L,Boiano J M,et al.Occupational silica exposure and risk of various diseases: an analysis using death certificates from 27 states of the United States[J].Occup Environ Med,2003,60(2): 122-129.
[3] Rees D,Murray J.Silica,silicosis and tuberculosis[J].Int J Tuberc Lung Dis,2007,11(5): 474-484.
[4] 李德鸿．加强预防措施研究 强化管理监督机制 为实现消除尘肺病而努力[J]．中华劳动卫生职业病杂志，2001，19(1)：1-2．
[5] Becklake M R.The mineral dust diseases[J].Tuber Lung Dis,1992,73(1): 13-20.
[6] Nadif R,Jedlicka A,Mintz M,et al.Effect of TNF and LTA polymorphisms on biological markers of response to oxidative stimuli in coal miners: a model of gene-environment interaction.Tumour necrosis factor and lymphotoxin alpha[J].J Med Genet,2003,40(2): 96-103.
[7] Risch N,Merikangas K.The future of genetic studies of complex human diseases[J].Science,1996,273(5281): 1516-1517.
[8] McCarthy J J,Hilfiker R.The use of single-nucleotide polymorphism maps in pharmacogenomics[J].Nat Biotechnol,2000,18(5): 505-508.
[9] McCanlies E,Landsittel D P,Yucesoy B,et al.Significance of genetic information in risk assessment and individual classification using silicosis as a case model[J].Ann Occup Hyg,2002,46(4): 375-381.
[10] Koskinen H,Tiilikainen A,Nordman H.Increased prevalence of HLA-Aw19 and of the phenogroup Aw19,B18 in advanced silicosis[J].Chest,1983,83(6): 848-852.
[11] Corbett E L,Mozzato-Chamay N,Butterworth A E,et al.Polymorphisms in the manor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners[J].Am J Respir Crit Care Med,2002,165(5): 690-693.
[12] Yucesoy B,Vallyathan V,Landsittel D P,et al.Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis[J].Toxicol Appl Pharmacol,2001,172(1): 75-82.
[13] 范雪云，李娟，王欣荣，等．转化生长因子-β(-509、+869、+915)位点基因多态性与尘肺易感性[J]．中华劳动卫生职业病杂志，2007，25(1)：1-4．
[14] 范雪云，王欣荣，李翠兰，等．白细胞介素-6基因多态性与尘肺易感性的病例对照研究[J]．中国职业医学，2007，34(3)：199-201，204．
[15] 范雪云，闫兆凤，闫进德，等．白细胞介素-1基因多态性与尘肺易感性的关系[J]．中华劳动卫生职业病杂志，2006，24(9)：526-530．
[16] 李霖，余晨，齐放，等．肿瘤坏死因子-a及其Ⅱ型受体基因多态性与矽肺[J]．中华劳动卫生职业病杂志，2004，22(5)：323-326．
[17] 王德军，杨跃林，夏庆杰，等．肿瘤坏死因子α基因多态性与矽肺遗传易感性的研究[J]．四川大学学报：医学版，2005，36(5)：679-682，712．
[18] 邹昌淇，邵强．为全球消除矽肺规划作出贡献[J]．中华劳动卫生职业病杂志，1999，17(1)：2-4．
[19] Wang X R,Christiani D C.Occupational lung disease in China[J].Int J Occup Environ Health,2003,9(4): 320-325.
[20] 李克，郑继烈．呼吸性矽尘容许限值的研究：有色金属矿山工人粉尘暴露与尘肺…[J]．中国工业医学杂志，1994，7(2)：68-71，93．
[21] Muir D C,Julian J A,Shannon H S,等.Silica exposure and silicosis among Ontario hardrock miners: Ⅲ.Analysis and risk estimates[J].Am J Ind Med,1989,16(1): 29-43.
[22] Hnizdo E,Sluis-Cremer G K.Risk of silicosis in a cohort of white South African gold miners[J].Am J Ind Med,1993,24(4): 447-457.
[23] 陈卫红，傅长汉．锡矿工人接尘与矽肺危险度评价[J]．中华劳动卫生职业病杂志， 1999，17(3)：131-134．
[24] U.S.Department of Health and Human Services.The health consequences of smoking: 25 years of progress-A report of the U.S.Surgeon General [J].1989.
[25] 孟昭阁，张国忱，邢国长．矿山矽肺与肺结核防治[J]．1985：1-150．
[26] 王簃兰，刚葆琪．现代劳动卫生学[J]．1994：103．
[27] Gamble J F,Hessel P A,Nicolich M.Relationship between silicosis and lung function[J].Scand J Work Environ Health,2004,30(1): 5-20.
[28] 张培元．为什么制定肺结核和非结核分支杆菌病诊治指南[J]．中华结核和呼吸杂志， 2001，24(2)：69-69．
[29] Hnizdo E,Churchyard G,Dowdeswel R.Lung function prediction equations derived from healthy South African gold miners[J].Occup Environ Med,2000,57(10): 698-705.
[30] 何仅瀛，林江涛．现代呼吸疾病诊断学[J]．2002：229-244．
[31] Davies P,Grange J.The genetics of host resistance and susceptibility to tuberculosis[J].Ann N Y Acad Sci,2001,953: 151-156.
[32] Gozal E,Ortiz L A,Zou X,et al.Silica-induced apoptosis in murine macrophage: involvement of tumor necrosis factor-alpha and nuclear factor-kappaB activation[J].Am J Respir Cell Mol Biol,2002,27(1): 91-98.
[33] Cowie R L.The epidemiology of tuberculosis in gold miners with silicosis[J].Am J Respir Crit Care Med,1994,150(5 Pt 1): 1460-1462.
[34] 何广学．现代结核病控制措施下结核病传染参数的研究[J]．中国防痨杂志，2002，24(6)：340-342．
[35] Wang X,Yano E.Pulmonary dysfunction in silica-exposed workers: a relationship to radiographic signs of silicosis and emphysema[J].Am J Ind Med,1999,36(2): 299-306.
[36] 胡克，陈喜兰，杨炯弥．弥漫性肺疾病临床诊断学[J]．2003：483-486．
[37] Srivastava K D,Rom W N,Jagirdar J,et al.Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice[J].Am J Respir Crit Care Med,2002,165(4): 527-533.
[38] Kang J L,Lee K,Castranova V.Nitric oxide up-regulates DNA-binding activity of nuclear factor-kappaB in macrophages stimulated with silica and inflammatory stimulants[J].Mol Cell Biochem,2000,215(1-2): 1-9.
[39] Kang J L,Pack I S,Lee H S,et al.Enhancelnent of nuclear factor-kappaB activation and protein tyrosine phosphorylation by a tyrosine phosphatase inhibitor,pervanadate,involves reactive oxygen species in silica-stimulated macrophages[J].Toxicology,2000,151(1-3): 81-89.
[40] Wonnhoudt L W,Commandeur J N,Vermeulen N P.Genetic polymorphisms of human N-acetyltransferase,cytochrome P450,glutathione-S-transferase,and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity[J].Crit Rev Toxicol,1999,29(1): 59-124.
[41] Sachidanandam R,Weissman D,Schmidt S C,et al.A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms[J].Nature,2001,409(6822): 928-933.
[42] Rimal B,Greenberg A K,Rom W N.Basic pathogenetic mechanisms in silicosis: current understanding[J].Curr Opin Pulm Med,2005,11 (2): 169-173.
[43] Jagirdar J,Begin R,Dufresne A,et al.Transforming growth factor-beta (TGF-beta) in silicosis[J].Am J Respir Crit Care Med,1996,154(4 Pt 1): 1076-1081.
[44] Barbarin V,Arras M,Misson P,et al.Characterization of the effect of interleukin-10 on silica-induced lung fibrosis in mice[J].Am J Respir Cell Mol Biol,2004,31(I): 78-85.
[45] Barbarin V,Xing Z,Delos M,et al.Puhnonary overexpression of IL-10 augments lung fibrosis and Th2 responses induced by silica particles[J].Am J Physiol Lung Cell Mol Physiol,2005,288(5): L841-848.
[46] Chen Y,Chen J,Dong J,et al.Antifibrotic effect of interferon gamma in silicosis model of rat[J].Toxicol Lett,2005,155(3): 353-360.
[47] Baroni T,Bodo M,D'Alessandro A,et al.Silica and its antagonistic effects on transforming growth factor-beta in lung fibroblast extracellular matrix production[J].J Investig Med,2001,49(2): 146-156.
[48] 陈莹，董静，陈杰．γ-干扰素对矽肺大鼠肿脏向介素-4和转化生长因子-β1蛋白表达的影响[J]．中华劳动卫生职业病杂志，2004，22(5)：350-353．
[49] Struhar D J,Harbeck R J,Gegen N,et al.Increased expression of class Ⅱ antigens of the major histocompatibility complex on alveolar macrophages and alveolar type Ⅱ cells and interleukin-1 (IL-1) secretion from alveolar macrophages in an animal model of silicosis[J].Clin Exp Immunol,1989,77(2): 281-284.
[50] Driscoll K E,Lindenschmidt R C,Maurer J K,et al.Pulmonary response to silica or titanium dioxide: inflammatory cells,alveolar macrophage-derived cytokines,and histopathology[J].Am J Respir Cell Mol Biol,1990,2(4): 381-390.
[51] Mohr C,Gemsa D,Graebner C,et al.Systemic macrophage stimulation in rats with silicosis: enhanced release of tumor necrosis factor-alpha from alveolar and peritoneal macrophages[J].Am J Respir Cell Mol Biol,1991,5(4): 395-402.
[52] Davis G S,Pfeiffer L M,Hemenway D R.Persistent overexpression of interleukin-lbeta and tumor necrosis factor-alpha in murine silicosis[J].J Environ Pathol Toxicol Oncol,1998,17(2): 99-114.
[53] Orfila C,Lepert J C,Gossart S,et al.Immunocytochemical characterization of lung macrophage surface phenotypes and expression of cytokines in acute experimental silicosis in mice[J].Histochem J,1998,30(12): 857-867.
[54] Piguet P F,Collart M A,Grau G E,et al.Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis [J].Nature,1990,344(6263): 245-247.
[55] Gossart S,Cambon C,Orfila C,et al.Reactive oxygen intermediates as regulators of TNF-alpha production in rat lung inflammation induced by silica[J].J Immunol,1996,156(4): 1540-1548.
[56] Fubini B,Hubbard A.Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis[J].Free Radic Biol Med,2003,34(12): 1507-1516.
[57] Gosset P,Lassalle P,Vanhee D,et al.Production of tumor necrosis factor-alpha and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust[J].Am J Respir Cell Mol Biol,1991,5(5): 431-436.
[58] Vanhee D,Gosset P,Boitelle A,et al.Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis[J].Eur Respir J,1995,8(5): 834-842.
[59] 冯国贤，南培宏．早期矽肺患者支气管肺泡灌洗液中生物标志物的研究[J]．中华劳动卫生职业病杂志，2000，18(4): 226-228.
[60] Zhang Y,Lee T C,Guillemin B,et al.Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure[J].J Immunol,1993,150(9): 4188-4196.
[61] Schmidt J A,Oliver C N,Lepe-Zuniga J L,et al.Silica-stimulated monocytes release fibroblast proliferation factors identical to interleukin 1.A potential role for interleukin 1 in the pathogenesis of silicosis[J].J Clin Invest,1984,73(5): 1462-1472.
[62] Savici D,He B,Geist L J,et al.Silica increases tumor necrosis factor (TNF) production,in part,by upregulating the TNF promoter[J].Exp Lung Res,1994,20(6): 613-625.
[63] 姬文婕，杨磊，王正伦，等．染矽尘小鼠肺组织中转化生长因子β1表达的逆转录聚合酶链反应检测[J]．中华劳动卫生职业病杂志，2003，21(3)：185-187．
[64] Olbruck H,Seemayer N H,Voss B,et al.Supernatants from quartz dust treated human macrophages stimulate cell proliferation of different human lung cells as well as collagen-synthesis of human diploid lung fibroblasts in vitro[J].Toxicology Letters,1998,96-97: 85-95.
[65] Denis M.Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis[J].Immunology,1994,82(4): 584-590.
[66] 姬文婕，程东军，杨磊．矽肺及矽尘作业工人生物监测指标的探讨[J]．中华劳动卫生职业病杂志，2005，23(3)：217-218．
[67] Huaux F,Louahed J,Hudspith B,et al.Role of interleukin-10 in the lung response to silica in mice[J].Am J Respir Cell Mol Biol,1998,18(1): 51-59.
[68] Ulloa L,Doody J,Massague J.Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway[J].Nature,1999,397(6721): 710-713.
[69] Ghosh A K,Yuan W,Mori Y,et al.Antagonistic regulation of type Ⅰ collagen gene expression by interferon-gamma and transforming growth factor-beta.Integration at the level of p300/CBP transcriptional coactivators[J].J Biol Chem,2001,276(14): 11041-11048.
[70] Abraham L J,Kroeger K M.Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease[J].J Leukoc Biol,1999,66(4): 562-566.
[71] Witte J S,Palmer L J,O'Connor R D,et al.Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma[J].Eur J Hum Genet,2002,10(1): 82-85.
[72] Schaaf B M,Seitzer U,Pravica V,et al.Tumor necrosis factor-alpha -308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer's lung patients[J].Am J Respir Crit Care Med,2001,163(2): 379-382.
[73] 王博蔚．肿瘤坏死因子基因多态性与疾病[J]．国外医学：免疫学分册，2000，23(2)：89-92．
[74] 徐旭雯，鲁猛厚．肿瘤坏死因子基因多态性与感染性疾病[J]．国外医学：生理病理科学与临床分册，2003，23(6)：653-656．
[75] 朱丽红，栾庆先．肿瘤坏死因子基因多态性与牙周炎[J]．国外医学：口腔医学分册，2005，32(2)：99-101．
[76] 周国胜，吴正祥．炎症性肠病与肿瘤坏死因子基因多态性的研究进展[J]．世界华人消化杂志，2008，16(21)：2390-2394．
[77] 曹倩，高敏，周刚，等．肿瘤坏死因子基因多态性与溃疡性结肠炎相关性研究[J]．中华消化杂志，2006，26(7)：460-463．
[78] Ates O,Hatemi G,Hamuryudan V,et al.Tumor necrosis factor-alpha and interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients[J].Clin Rheumatol,2008,27(10): 1243-1248.
[79] Whyte M,Hubbard R,Meliconi R,et al.Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms[J].Am J Respir Crit Care Med,2000,162(2 Pt 1): 755-758.
[80] 孙智霞，姚三巧，范雪云．肿瘤坏死因子基因多态性与纤维化性疾病的相关性[J]．中国职业医学，2004，31(5)：57-58．
[81] Libura J,Bettens F,Radkowski A,et al.Risk of chemotherapy-induced pulmonary fibrosis is associated with polymorphic tumour necrosis factor-a2 gene[J].Eur Respir J,2002,19(5): 912-918.
[82] Riha R L,Yang I A,Rabnott G C,et al.Cytokine gene polymorphisms in idiopathic pulmonary fibrosis[J].Intern Med J,2004,34(3): 126-129.
[83] Zhai R,Jetten M,Schins R P,et al.Polymorphisms in the promoter of the tumor necrosis factor-alpha gene in coal miners[J].Am J Ind Med,1998,34(4): 318-324.
[84] Kim K A,Cho Y Y,Cho J S,et al.Tumor necrosis factor-alpha gene promoter polylnorphism in coal workers' pneumoconiosis[J].Mol Cell Biochem,2002,234-235(1-2): 205-209.
[85] Yucesoy B,Vallyathan V,Landsittel D P,et al.Cytokine polymorphisms in silicosis and other pneumoconioses[J].Mol Cell Biochem,2002,234-235(1-2): 219-224.
[86] Majetschak M,Flohe S,Obertacke U,et al.Relation of a TNF gene polymorphism to severe sepsis in trauma patients[J].Ann Surg,1999,230(2): 207-214.
[87] Yamaguchi E,Itoh A,Hizawa N,et al.The gene polymorphism of tumor necrosis factor-beta,but not that of tumor necrosis factor-alpha,is associated with the prognosis of sarcoidosis[J].Chest,2001,119(3): 753-761.
[88] Bettinotti M P,Hartung K,Deicher H,et al.Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythelnatosus: TNFB-MHC haplotypes[J].Immunogenetics,1993,37(6): 449-454.
[89] Lu L Y,Cheng H H,Sung P K,et al.Tumor necrosis factor-beta +252A polymorphism is associated with systemic lupus erythematosus in Taiwan[J].J Fonnos Med Assoc,2005,104(8): 563-570.
[90] Nonomura N,Tokizane T,Nakayama M,et al.Possible correlation between polymorphism in the tumor necrosis factor-beta gene and the clinicopathological features of bladder cancer in Japanese patients[J].Int J Urol,2006,13(7): 971-976.
[91] Shimura T,Hagihara M,Takebe K,et al.The study of tumor necrosis factor beta gene polymorphism in lung cancer patients[J].Cancer,1994,73(4): 1184-1188.
[92] Grainger D J,Heathcote K,Chiano M,et al.Genetic control of the circulating concentration of transforming growth factor type betal[J].Hum Mol Genet,1999,8(1): 93-97.
[93] Yamada Y,Miyauchi A,Goto J,et al.Association of a polymorphism of the transforming growth factor-betal gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women[J].J Bone Miner Res,1998,13(10): 1569-1576.
[94] Awad M R,El-Gamel A,Hasleton P,et al.Genotypic variation in the transforming growth factor-betal gene: association with transforming growth factor-betal production,fibrotic lung disease,and graft fibrosis after lung transplantation[J].Transplantation,1998,66(8): 1014-1020.
[95] El-Gamel A,Awad M R,Hasleton P S,et al.Transforming growth factor-beta (TGF-betal) genotype and lung allograft fibrosis[J].J Heart Lung Transplant,1999,18(6): 517-523.
[96] Xaubet A,Marin-Arguedas A,Lario S,et al.Transforming growth factor-betal gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med.2003.168(4): 431-435.
[97] 吕铁明，谭建明，等．细胞因子基因多态性与细胞因子水平关系的研究[J]．中华器官移植杂志，2002，23(5)：266-268．
[98] 刘庆华，辛洪涛．转化生长因子-β与肺纤维化[J]．国外医学：内科学分册，2002，29(8)：339-340，355．
[99] 姚武，郝长付，吴逸明，等．转化生长因子β1血清浓度及基因多态性与煤工尘肺的关系[J]．中国职业医学，2006，33(4)：265-268．
[100] 姚武，郝长付，王娜，等．转化生长因子β1基因多态性对煤工尘肺遗传易感性的影响[J]．现代预防医学，2006，33(10)：1875-1877．
[101] Asadullah K,Sterry W,Volk H D.Interleukin-10 therapy--review of a new approach[J].Pharmacol Rev,2003,55(2): 241-269.
[102] Turner D M,Williams D M,Sankaran D,et al.An investigation of polymorphism in the interleukin- 10 gene promoter[J].Eur J Immunogenet,1997,24(1): 1-8.
[103] Kurreeman F A,Schonkeren J J,Heijmans B T,et al.Transcription of the ILl0 gene reveals allele-specific regulation at the mRNA level[J].Hum Mol Genet,2004,13(16): 1755-1762.
[104] Edwards-Smith C J,Jonsson J R,Purdie D M,et al.Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa[J].Hepatology,1999,30(2): 526-530.
[105] Henri S,Chevillard C,Mergani A,et al.Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease[J].J Immunol,2002,169(2): 929-936.
[106] Pastor I J,Laso F J,Romero A,et al.-238 G＞A polymorphism of tumor necrosis factor alpha gene (TNFA) is associated with alcoholic liver cirrhosis in alcoholic Spanish men[J].Alcohol Clin Exp Res,2005,29(11): 1928-1931.
[107] Warzocha K,Ribeiro P,Bienvenu J,et al.Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome[J].Blood,1998,91(10): 3574-3581.
[108] Um J Y,Moon K S,Lee K M,et al.Association of interleukin-1 alpha gene polymorphism with cerebral infarction[J].Brain Res Mol Brain Res,2003,115(1): 50-54.
[109] Lu W,Pan K,Zhang L,et al.Genetic polymorphisms of interleukin (IL)-1B,IL-1RN,IL-8,IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population[J].Carcinogenesis,2005,26(3): 631-636.
[110] di Giovine F S,Takhsh E,Blakemore A I,et al.Single base polymorphism at -511 in the human intefleukin-1 beta gene (IL1 beta)[J].Hum Mol Genet,1992,1(6): 450.
[111] Pociot F,Molvig J,Wogensen L,et al.A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro[J].Eur J Clin Invest,1992,22(6): 396-402.
[112] Tarlow J K,Blakemore A I,Lennard A,et al.Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat[J].Hum Genet,1993,91(4): 403-404.
[113] Caserta T M,Knisley A A,Tan F K,et al.Genotypic analysis of the TGF beta-509 allele in patients with systemic lupus erythematosus and Sjogren's syndrome[J].Ann Genet,2004,47(4): 359-363.
[114] Amani D,Dehaghani A S,Zolghadri J,et al.Lack of association between the TGF-beta1 gene polymorphisms and recurrent spontaneous abortion[J]. J Reprod Immunol, 2005,68(1-2): 91-103.
[115] Ma S L, Tang N L, Lam L C, et al. The association between promoter polymorphism of the interleukin-10 gene and Alzheimer's disease[J]. Neurobiol Aging, 2005, 26(7):1005-1010.
[116] Chang Y H, Huang C N, Wu C Y, et al. Association of interleukin-10 A-592C and T-819C polymorphisms with type 2 diabetes mellitus[J]. Hum Immunol, 2005, 66(12):1258-1263.
[117] Zambon C F, Basso D, Navaglia F, et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome[J].Cytokine, 2005, 29(4): 141-152.
[118] 张忠彬,朱人,夏昭林.应用CRS—RFLP 技术检测 hOGGlc.326 位点的单核苷酸多态性[J]. 中国工业医学杂志,2004, 17(5): 293-296.
[119] Shi Y Y, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci[J].Cell Res, 2005, 15(2): 97-98.
[120] Machado J C, Pharoah P, Sousa S, et al. Interleukin lB and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma[J].Gastroenterology, 2001, 121(4): 823-829.
[121] Ding M, Chen F, Shi X, et al. Diseases caused by silica: mechanisms of injury and disease development[J]. Int Immunophannacol, 2002, 2(2-3): 173-182.
[122] Stuber F, Petersen M, Bokelmann F, et al. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis[J]. Crit Care Med, 1996, 24(3): 381-384.
[123] Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans[J]. Clin Exp Immunol, 1998, 113(3): 401-406.
[124] Bouma G, Crusius J B, Oudkerk Pool M, et al. Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease[J]. Scand J Immunol, 1996, 43(4):456-463.
[125] Wilson A G, di Giovine F S, Blakemore A I, et al. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by Ncol restriction of PCR product[J]. Hum Mol Genet, 1992, 1(5): 353.
[126] Hajeer A H, Hutchinson I V. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease[J]. Hum Immunol, 2001, 62(11): 1191-1199.
[127] Brinkman B M, Giphart M J, Verhoef A, et al. Tumor necrosis factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome[J].Hum Immunol, 1994, 41(4): 259-266.
[128] Brinkman B M, Kaijzel E L, Huizinga T W, et al. Detection of a C-insertion polymorphism within the human tumor necrosis factor alpha (TNFA) gene[J]. Hum Genet,1995, 96(4): 493.
[129] D'Alfonso S, Richiardi P M. A polymorphic variation in a putative regulation box of the TNFA promoter region[J]. Immunogenetics, 1994,39(2): 150-154.
[130] Hamann A, Mantzoros C, Vidal-Puig A, et al. Genetic variability in the TNF-alpha promoter is not associated with type Ⅱ diabetes mellitus (NIDDM)[J]. Biochem Biophys Res Commun, 1995,211(3): 833-839.
[131] Higuchi T, Seki N, Kamizono S, et al. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese[J]. Tissue Antigens, 1998,51(6): 605-612.
[132] Uglialoro A M, Turbay D, Pesavento P A, et al. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter[J].Tissue Antigens, 1998, 52(4): 359-367.
[133] Zimmerman P A, Guderian R H, Nutman T B. A new TNFA promoter allele identified in South American Blacks[J]. Immunogenetics, 1996, 44(6): 485-486.
[134] Bayley J P, de Rooij H, van den Elsen P J, et al. Functional analysis of linker-scan mutants spanning the -376, -308, -244, and -238 polymorphic sites of the TNF-alpha promoter[J].Cytokine,2001,14(6): 316-323.
[135] Frigerio S,Ciusani E,Pozzi A,et al.Tumor necrosis factor microsatellite polymorphisms in Italian glioblastoma patients[J].Cancer Genet Cytogenet,1999,109(2): 172-174.
[136] Kroeger K M,Carville K S,Abraham L J.The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription[J].Mol Immunol,1997,34(5): 391-399.
[137] Messer G,Spengler U,Jung M C,et al.Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production[J].J Exp Med,1991,173(1): 209-219.
[138] 王德军，杨跃林，夏庆杰，等．肿瘤坏死因子α基因多态性与矽肺的相关性[J]．职业卫生与病伤，2005，20(1)：1-4．
[139] Meenagh A,Williams F,Ross O A,et al.Frequency of cytokine polymorphisms in populations from western Europe,Africa,Asia,the Middle East and South America[J].Hum Immunol,2002,63(11): 1055-1061.
[140] 陈雅萍，宋志芳．脂类介质、细胞因子与矽肺炎症、纤维化[J]．职业卫生与病伤，1999，14(1)：48-51．
[141] Kolb M,Margetts P J,Anthony D C,et al.Transient expression of IL-lbeta induces acute lung injury and chronic repair leading to pulmonary fibrosis[J].J Clin Invest,2001,107(12): 1529-1536.
[142] Hulkkonen J,Laippala P,Hurme M.A rare allele combination of the interleukin-1 gene complex is associated with high interleukin-1 beta plasma levels in healthy individuals[J].Eur Cytokine Netw,2000,11(2): 251-255.
[143] El-Omar E M,Carrington M,Chow W H,et al.Interleukin-1 polymorphisms associated with increased risk of gastric cancer[J].Nature,2000,404(6776): 398-402.
[144] Hamajima N,Matsuo K,Saito T,et al.Interleukin 1 polymorphisms,lifestyle factors,and Helicobacter pylori infection[J].Jpn J Cancer Res,2001,92(4): 383-389.
[145] Chang Y W,Jang J Y,Kim N H,et al.Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer[J].Int J Cancer,2005,114(3): 465-471.
[146] Takamatsu M,Yamauchi M,Maezawa Y,et al.Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients[J].Am J Gastroenterol,2000,95(5): 1305-1311.
[147] Gaeta G,De Michele M,Cuomo S,et al.Arterial abnormalities in the offspring of patients with premature myocardial infarction[J].N Engl J Med,2000,343(12): 840-846.
[148] Wood N A,Thomson S C,Smith R M,et al.Identification of human TGF-betal signal (leader) sequence polymorphisms by PCR-RFLP[J].J Immunol Methods,2000,234(1-2): 117-122.
[149] Zhou X,Tan F K,Stivers D N,et al.Microsatellites and intragenic polymorphisms of transforming growth factor beta and platelet-derived growth factor and their receptor genes in Native Americans with systemic sclerosis (scleroderma): a preliminary analysis showing no genetic association[J].Arthritis Rheum,2000,43(5): 1068-1073.
[150] Bayat A,Bock O,Mrowietz U,et al.Genetic susceptibility to keloid disease and hypertrophic scarring: transforming growth factor betal common polymorphisms and plasma levels[J].Plast Reconstr Surg,2003,111(2): 535-543; discussion 544-536.
[151] Yang Y H,Lai H J,Kao C K,et al.The association between transforming growth factor-beta gene promoter C-509T polymorphism and Chinese children with Henoch-Schonlein purpura[J].Pediatr Nephrol,2004,19(9): 972-975.
[152] Yokota M,Ichihara S,Lin T L,et al.Association of a T29--＞C polymorphism of the transforming growth factor-betal gene with genetic susceptibility to myocardial infarction in Japanese[J].Circulation,2000,101 (24): 2783-2787.
[153] Arkwright P D,Laurie S,Super M,et al.TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis[J].Thorax,2000,55(6): 459-462.
[154] Gewaltig J,Mangasser-Stephan K,Gartung C,et al.Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis[J].Clin Chim Acta,2002,316(1-2): 83-94.
[155] Eskdale J,Kube D,Tesch H,et al.Mapping of the human IL10 gene and further characterization of the 5'flanking sequence[J].Immunogenetics,1997,46(2): 120-128.
[156] Lazarus M,Hajeer A H,Turner D,et al.Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus[J].J Rheumatol,1997,24(12): 2314-2317.
[157] Tagore A,Gonsalkorale W M,Pravica V,et al.Interleukin-10 (IL-10) genotypes in inflammatory bowel disease[J].Tissue Antigens,1999,54(4): 386-390.
[158] Faupel-Badger J M,Kidd L C,Albanes D,et al.Association of IL-10 polymorphisms with prostate cancer risk and grade of disease[J].Cancer Causes Control,2008,19(2): 119-124.
[159] Lech-Maranda E,Baseggio L,Charlot C,et al.Genetic polymorphisms in the proximal IL-10 promoter and susceptibility to non-Hodgkin lymphoma[J].Leuk Lymphoma,2007,48(11): 2235-2238.
[160] Castro-Santos P,Suarez A,Lopez-Rivas L,et al.TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease.Association of-1082 AA low producer IL-10 genotype with steroid dependency[J].Am J Gastroenterol,2006,101(5): 1039-1047.
[161] Hajeer A H,Lazarus M,Turner D,et al.IL-10 gene promoter polymorphisms in rheumatoid arthritis[J].Scand J Rheumatol,1998,27(2): 142-145.
[162] Eskdale J,Wordsworth P,Bowman S,et al.Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus[J].Tissue Antigens,1997,49(6): 635-639.
[163] 张平交，李艳，杨相会．白细胞介素10基因启动子区多态性与乙型肝炎病毒感染预后的关联研究[J]．中华医学遗传学杂志，2006，23(4)：410-414．
[164] Hulkkonen J,Pertovaara M,Antonen J,et al.Genetic association between interleukin-10 promoter region polymorphisms and primary Sjogren's syndrome[J].Arthritis Rheum,2001,44(1): 176-179.
[165] Kusumoto K,Uto H,Hayashi K,et al.Interleukin-10 or tumor necrosis factor-alpha polymorphisms and the natural course of hepatitis C virus infection in a hyperendemic area of Japan[J].Cytokine,2006,34(1-2): 24-31.
[166] Chevillard C,Henri S,Stefani F,et al.Two new polymorphisms in the human interferon gamma (IFN-gamma) promoter[J].Eur J Immunogenet,2002,29(1): 53-56.
[167] Henri S,Stefani F,Parzy D,et al.Description of three new polymorphisms in the intronic and 3'UTR regions of the human interferon gamma gene[J].Genes hnmun,2002,3(1): 1-4.
[168] Pravica V,Perrey C,Stevens A,et al.A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production[J].Hum Immunol,2000,61(9): 863-866.
[169] 李志方，卢健红，李景柔，等．Ifn-γ基因多态性与小儿哮喘的相关性[J]．中国优生与遗传杂志，2006，14(9)：22-23．
[170] 张平安，吴健民，李艳．干扰素γ基因内含子1+874位点多态性与乙型肝炎病毒感染关系的研究[J]．中华流行病学杂志，2006，27(1)：41-43．
[171] Ding S,Li L,Zhu X.Polymorphism of the interferon-gamma gene and risk of tuberculosis in a southeastern Chinese population[J].Hum Immunol,2008,69(2): 129-133.
[172] 朱启镕，俞慧，顾绍庆，等．干扰素γ和肿瘤坏死因子α基因单核苷酸多态性与宫内乙肝病毒感染易感性研究[J]．临床儿科杂志，2005．23(7)：446-449．
[173] Hessel P A,Gamble J F,Nicolich M.Relationship between silicosis and smoking[J].Scand J Work Environ Health,2003,29(5): 329-336.
[174] Castranova V,Porter D,Millecchia L,et al.Effect of inhaled crystalline silica in a rat model: time course of pulmonary reactions[J].Mol Cell Biochem,2002,234-235(1-2): 177-184.
[175] Porter D W,Ye J,Ma J,et al.Time course of puhnonary response of rats to inhalation of crystalline silica: NF-kappa B activation,inflammation,cytokine production,and damage[J].Inhal Toxicol,2002,14(4): 349-367.
[176] Hubbard A K,Timblin C R,Shukla A,et al.Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice[J].Am J Physiol Lung Cell Mol Physiol,2002,282(5): L968-975.
[177] Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B[J].Annu Rev Cell Biol, 1994, 10: 405-455.
[178] 叶进燕,陈少贤.核因子 κ b 与肺部疾病[J]. 国外医学:内科学分册, 2004,31(1):29-33.
[179] Baldwin A S, Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights[J].Annu Rev Immunol, 1996, 14: 649-683.
[180] May M J, Ghosh S. Signal transduction through NF-kappa B[J]. Immunol Today, 1998,19(2): 80-88.
[181] Karban A S, Okazaki T, Panhuysen C I, et al. Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis[J]. Hum Mol Genet, 2004,13(1): 35-45.
[182] Conne B, Stutz A, Vassalli J D. The 3' untranslated region of messenger RNA: A molecular ‘hotspot' for pathology?[J]. Nat Med, 2000, 6(6): 637-641.
[183] Szamosi T, Lakatos P L, Szilvasi A, et al. The 3'UTR NFKBIA variant is associated with extensive colitis in Hungarian IBD patients[J]. Dig Dis Sci, 2009, 54(2): 351-359.
[184] Hong J, Leung E, Fraser A G, et al. Polymorphisms in NFKBIA and ICAM-1 genes in New Zealand Caucasian Crohn's disease patients[J]. J Gastroenterol Hepatol, 2007,22(10): 1666-1670.
[185] Gao J, Pfeifer D, He L J, et al. Association of NFKBIA polymorphism with colorectal cancer risk and prognosis in Swedish and Chinese populations[J]. Scand J Gastroenterol,2007, 42(3): 345-350.
[186] Klein W, Tromm A, Folwaczny C, et al. A polymorphism of the NFKBIA gene is associated with Crohn's disease patients lacking a predisposing allele of the CARD15 gene[J]. Int J Colorectal Dis, 2004, 19(2): 153-156.
[187] Kim L H, Shin H D, Park B L, et al. Identification of variants in NFKBIA and association analysis with hepatocellular carcinoma risk among chronic HBV patients[J]. Hum Mutat,2003, 21(6): 652-653.
[188] Parker K M, Ma M H, Manyak S, et al. Identification of polymorphisms of the IkappaBalpha gene associated with an increased risk of multiple myeloma[J]. Cancer Genet Cytogenet, 2002, 137(1): 43-48.
[189] Leshinsky-Silver E, Karban A, Cohen S, et al. Lack of association of the 3'-UTR polymorphism in the NFKBIA gene with Crohn's disease in an Israeli cohort[J]. Int J Colorectal Dis, 2007, 22(9): 1021-1025.
[190] Curran J E, Weinstein S R, Griffiths L R. Polymorphic variants of NFKB1 and its inhibitory protein NFKBIA, and their involvement in sporadic breast cancer[J]. Cancer Lett, 2002, 188(1-2): 103-107.
[191] Lin S C, Liu C J, Yeh W I, et al. Functional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewers[J]. Cancer Lett, 2006,243(1): 47-54.
[192] Mossman B T, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis[J].Am J Respir Crit Care Med, 1998, 157(5 Pt 1): 1666-1680.
[193] Hamilton R F, Jr., Pfau J C, Marshall G D, et al. Silica and PM1648 modify human alveolar macrophage antigen-presenting cell activity in vitro[J]. J Environ Pathol Toxicol Oncol, 2001, 20 Suppl 1: 75-84.
[194] Yamamoto Y, Gaynor R B. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer[J]. J Clin Invest, 2001,107(2): 13(?)-142.
[195] Senftleben U, Cao Y, Xiao G, et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway[J]. Science, 2001, 293(5534): 1495-1499.
[196] Jungnickel B, Staratschek-Jox A, Brauninger A, et al. Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma[J]. J Exp Med, 2000,191(2): 395-402.
[197] Beg A A, Sha W C, Bronson R T, et al. Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice[J]. Genes Dev,1995, 9(22): 2736-2746.
[198] Hochwald S N, Lind D S, Malaty J, et al. Antineoplastic therapy in colorectal cancer through proteasome inhibition[J]. Am Surg, 2003, 69(1): 15-23.
[199] Scaife C L, Kuang J, Wills J C, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis[J]. Cancer Res,2002, 62(23): 6870-6878.
[200] Bonn M E, van Bodegraven A A, Mulder C J, et al. A NFKB1 promoter polymorphism is involved in susceptibility to ulcerative colitis[J]. Int J Immunogenet, 2005, 32(6):401-405.
[201] Oliver J, Gomez-Garcia M, Paco L, et al. A functional polymorphism of the NFKB1 promoter is not associated with ulcerative colitis in a Spanish population[J]. Inflamm Bowel Dis, 2005, 11(6): 576-579.
[202] Kurylowicz A, Hiromatsu Y, Jurecka-Lubieniecka B, et al. Association of NFKB1 -94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease[J]. Genes Immun, 2007, 8(7): 532-538.
[203] Lewander A, Butchi A K, Gao J, et al. Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations[J]. Scand J Gastroenterol, 2007, 42(11): 1332-1338.
[204] Riemann K, Becker L, Struwe H, et al. Insertion/deletion polymorphism in the promoter of NFKB1 as a potential molecular marker for the risk of recurrence in superficial bladder cancer[J]. Int J Clin Pharmacol Ther, 2007, 45(8): 423-430.
[205] Lo S S, Chen J H, Wu C W, et al. Functional polymorphism of NFKB1 promoter may correlate to the susceptibility of gastric cancer in aged patients[J]. Surgery, 2009, 145(3):280-285.
[206] Zhou B, Rao L, Li Y, et al. A functional insertion/deletion polymorphism in the promoter region of NFKB1 gene increases susceptibility for nasopharyngeal carcinoma[J]. Cancer Lett, 2009, 275(1): 72-76.
[207] Bu H, Rosdahl I, Sun X F, et al. Importance of polymorphisms in NF-kappaBl and NF-kappaBIalpha genes for melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients[J]. J Cancer Res Clin Oncol, 2007, 133(11):859-866.
[208] Mirza M M, Fisher S A, Onnie C, et al. No association of the NFKB1 promoter polymorphism with ulcerative colitis in a British case control cohort[J]. Gut, 2005, 54(8):1205-1206.
[209] Glas J, Torok H P, Tonenchi L, et al. Role of the NFKB1 -94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes[J]. Inflamm Bowel Dis, 2006, 12(7):606-611.
[210] Kosoy R, Concannon P. Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes[J]. Genes Immun, 2005, 6(3): 231-235.
[211] Orozco G, Sanchez E, Collado M D, et al. Analysis of the functional NFKB1 promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus[J]. Tissue Antigens, 2005, 65(2): 183-186.
[212] Martin J, Perez-Annengol C, Miranda-Filloy J A, et al. Lack of association of a functional -94ins/delATTG NFKB1 promoter polymorphism with susceptibility and clinical expression of biopsy-proven giant cell arteritis in northwest Spain[J]. J Rheumatol, 2006,33(2): 285-288.
[213] Rueda B, Nunez C, Lopez-Nevot M A, et al. Functional polymorphism of the NFKB1 gene promoter is not relevant in predisposition to celiac disease[J]. Scand J Gastroenterol,2006, 41(4): 420-423.
[214] Riemann K, Becker L, Struwe H, et al. No association of the NFKB1 insertion/deletion promoter polymorphism with survival in colorectal and renal cell carcinoma as well as disease progression in B-cell chronic lymphocytic leukemia[J]. Pharmacogenet Genomics,2006, 16(11): 783-788.
[215] 汪望月,夏冰,李春,等.核因子 κ b 抑制因子 α基因多态性与胃癌的相关性研究[J].中华胃肠外科杂志, 2007, 10(6): 585-586.
[216] Domagala-Kulawik J, Droszcz P, Kraszewska I, et al. Expression of Fas antigen in the cells from bronchoalveolar lavage fluid (BALF)[J]. Folia Histochem Cytobiol, 2000,38(4): 185-188.
[217] Kuwano K, Hagimoto N, Kawasaki M, et al. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis[J]. J Clin Invest, 1999, 104(1): 13-19.
[218] Borges V M,Falcao H,Leite-Junior J H,et al.Fas ligand triggers pulmonary silicosis[J].J Exp Med,2001,194(2): 155-164.
[219] Shen H M,Zhang Z,Zhang Q F,et al.Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages[J].Am J Physiol Lung Cell Mol Physiol,2001,280(1): L10-17.
[220] Borges V M,Lopes M F,Falcao H,et al.Apoptosis underlies immunopathogenic mechanisms in acute silicosis[J].Am J Respir Cell Mol Biol,2002,27(1): 78-84.
[221] Otsuki T,Miura Y,Nishimura Y,et al.Alterations of Fas and Fas-related molecules in patients with silicosis[J].Exp Biol Med (Maywood),2006,231(5): 522-533.
[222] 袁宝军，刘志忠，丁秀荣，等．煤工尘肺患者血清中可溶性Fas和FasL水平及临床意义[J]．中华劳动卫生职业病杂志，2006，24(2)：96-98．
[223] Bel Hadj Jrad B,Mahfouth W,Bouaouina N,et al.A polymorphism in FAS gene promoter associated with increased risk of nasopharyngeal carcinoma and correlated with anti-nuclear autoantibodies induction [J].Cancer Lett,2006,233 (1): 21-27.
[224] Sun T,Miao X,Zhang X,et al.Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma[J].J Natl Cancer Inst,2004,96(13): 1030-1036.
[225] Wu J,Metz C,Xu X,et al.A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients[J].J Immunol,2003,170(1): 132-138.
[226] Li C,Wu W,Liu J,et al.Functional polymorphisms in the promoter regions of the FAS and FAS ligand genes and risk of bladder cancer in south China: a case-control analysis[J].Pharmacogenet Genomics,2006,16(4): 245-251.
[227] Takahashi T,Tanaka M,Inazawa J,et al.Human Fas ligand: gene structure,chromosomal location and species specificity[J].Int Immunol,1994,6(10): 1567-1574.
[228] Qiu L X,Shi J,Yuan H,et al.FAS -1,377 G/A polymorphism is associated with cancer susceptibility: evidence from 10,564 cases and 12,075 controls[J].Hum Genet,2009.
[229] Chen J Y,Wang C M,Ma C C,et al.The -844C/T polymorphism in the Fas ligand promoter associates with Taiwanese SLE[J].Genes Immun,2005,6(2): 123-128.
[230] Farre L,Bittencourt A L,Silva-Santos G,et al.Fas 670 promoter polymorphism is associated to susceptibility,clinical presentation,and survival in adult T cell leukemia[J].J Leukoc Biol,2008,83(1): 220-222.
[231] Kanemitsu S,Ihara K,Saifddin A,et al.A functional polymorphism in fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus[J].J Rheumatol,2002,29(6): 1183-1188.
[232] Kordi Tamandani D M,Sobti R C,Shekari M.Association of Fas-670 gene polymorphism with risk of cervical cancer in North Indian population[J].Clin Exp Obstet Gynecol,2008,35(3): 183-186.
[233] Kang S,Dong S M,Seo S S,et al.FAS -1377 G/A polymorphism and the risk of lymph node metastasis in cervical cancer[J].Cancer Genet Cytogenet,2008,180(1): 1-5.
[234] Sun T,Zhou Y,Li H,et al.FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer[J].J Exp Med,2005,202(7): 967-974.
[235] Dybikowska A,Sliwinski W,Emerich J,et al.Evaluation of Fas gene promoter polymorphism in cervical cancer patients[J].Int J Mol Med,2004,14(3): 475-478.
[236] Engelmark M T,Renkema K Y,Gyllensten U B.No evidence of the involvement of the Fas -670 promoter polymorphism in cervical cancer in situ[J].Int J Cancer,2004,112(6): 1084-1085.
[237] Erdogan M,Karadeniz M,Berdeli A,et al.Fas/Fas ligand gene polymorphism in patients with papillary thyroid cancer in the Turkish population[J].J Endocrinol Invest,2007,30(5): 411-416.
[238] Gormus U,Ergen A,Yaylim-Eraltan I,et al.Fas-1377 A/G polymorphism in lung cancer[J].In Vivo,2007,21(4): 663-666.
[239] Huang Q R,Manolios N.Investigation of the -1377 polymorphism on the Apo-1/Fas promoter in systemic lupus erythematosus patients using allele-specific amplification[J].Pathology,2000,32(2): 126-130.
[1] 金泰廙，孙贵范，主编．职业卫生与职业医学[M]．北京：人民卫生出版社，2003，248-272．
[2] Kim KA,Cho YY,Cho JS,et al.Tumor necrosis factor-alpha gene promoter polymorphism in coal workers' pneumoconiosis [J].Mol Cell Biochem,2002,234-235(1-2):205-209.
[3] Corbett EL,Mozzato CN,Butterworth AE,et al.Polymorphisms in the tumor necrosis factor-α gene promoter may predispose to severe silicosis in black South African miners [J].Am J Respir Crit Care Med,2002,165(5): 690-693.
[4] 李霖，余晨，齐放，等．肿瘤坏死冈子-α及其Ⅱ型受体基因多态性与煤工尘肺[J]．中华劳动卫生职业病杂志，2004，22(4)：241-244．
[5] 李霖，余晨，齐放，等．肿瘤坏死因子-α及其Ⅱ型受体基因多态性与矽肺[J]．中华劳动卫生职业病杂志，2004，22(5)：323-326．
[6] 王德军，杨跃林，夏庆杰，等．肿瘤坏死因子-α基因多态性与矽肺遗传易感性的研究[J]．四川大学学报(医学版)，2005，36(5)：679-682．
[7] Wang XT,Ohtsuka Y,Kimura K.Antithetical effect of tumor necrosis factor-alpha gene polymorphism on coal workers' pneumoconiosis (CWP) [J].Am J Ind Med,2005,48(1):24-29.
[8] Meenagh A,Williams F,Ross OA,et al.Frequency of cytokine polymorphisms in populations from western Europe,Africa,Asia,the Middle East and South America [J].Hum Immunol,2002,63(11):1055-1061.
[9] 李娟．转化生长因子-β及基因多态性与纤维化的关系[J]．中华劳动卫生职业病杂志，2004，22(5)：382-385．
[10] Grainger D J,Heathcote K,Chiano M,et al.Genetic control of the circulating concentration of transforming growth factor type β1 [J].Hum Mol Genet,1999,8(1):93-97.
[11] Yamada Y,Miyauchi A,Goto J,et al.Association of a polymorphism of the transforming growth factor-beta 1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women [J].J Bone Miner Res,1998,13(10):1569-1576.
[12] Awad MR,El-Gamel A,Hasleton P,et al.Genotypic variation in the transforming growth factor-beta 1 gene: association with transforming growth factor-betal production,fibrotic lung disease,and graft fibrosis after lung transplantation [J].Transplantation,1998,66(8): 1014-1020.
[13] El-Gamel A,Awad MR,Hasleton PS,et al.Transforming growth factor-beta (TGF-beta 1) genotype and lung allograft fibrosis [J].J Heart Lung Transplant,1999,18(6):517-523.
[14] Arkwright PD,Laurie S,Super M,etal.TGF-β1 genotype and accelerated decline in lung function of patients with cystic fibrosis [J].Thorax,2000,55(6):459-462.
[15] Xaubet A,Main-Arguedas A,Lario S,et al.Transforming growth factor-beta 1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis [J].Am J Respir Crit Care Med,2003,168(4):431-435.
[16] 姚武，王治明，王绵珍等．煤工尘肺患者血清转化生长因子β1水平与其基因多态性的关系研究[J]．四川大学学报(医学版)，2005，36(6)：827-829．
[17] Yucesoy B,Vallyathan V,Landsittel DP,et al.Association of tumor necrosis factor and interleukin-1 gene polymorphisms with silicosis [J].Toxicol Appl Pharmacol,2001,172(1):75-82.
[18] Yucesoy B,Vallyathan V,Landsittel DP,et al.Polymorphislns of the IL-1 gene complex in coal miners with silicosis [J].Am J Ind Med,2001,39(3):286-291.
[19] 王明臣，刘红春，王俊萍等．煤工尘肺患者血清白细胞介素6及其可溶性受体含量的变化[J]．中国职业医学，2004，31(1)：25-26．
[20] Zhai R,Liu G,Ge X,et al.Serum levels of tumor necrosis factor-alpha (TNF-alpha),interleukin 6 (IL-6),and their soluble receptors in coal workers' pneumoconiosis [J].Respir Med,2002,96(10):829-834.
[21] Zhai R,Liu G,Yang C,et al.The G to C polyanorphism at -174 of the interleukin-6 gene is rare in a Southern Chinese population [J].Pharmacogenetics,2001,11(8): 699-701.
[22] Rihs HP,Lipps P,May-Taube K,et al.Immunogenetic studies on HLA-DR in German coal miners with and without coal worker's pneumoconiosis [J].Lung,1994,172(6):347-354.
[23] 李建强，宋满景，彭则．我国山西汉族煤工尘肺患者HLA-DRB1等位基因的调查[J]．中华劳动卫生职业病杂志，1999，17(2)：105-106．
[24] 袁宝军，张志欣，幸宏芬等．矽肺与人类白细胞抗原-DRB1~*和-DQB1~*基因相关性的研究[J]．中华劳动卫生职业病杂志，2002，20(2)：93-96．
[25] Zhai R.Liu G.Ge X,et al.Genetic polymorphisms of MnSOD,GSTM1,GSTT1,and OGG1 in coal workers' pneumoconiosis [J].J Occup Environ Med,2002,44(4):372-377.
[26] Yucesoy B,Johnson VJ,Kashon ML.Lack of association between antioxidant gene polymorphisms and progressive massive fibrosis in coal miners[J].Thorax,2005,60(6):492-495.
[2] Calvert G M,Rice F L,Boiano J M,et al.Occupational silica exposure and risk of various diseases: an analysis using death certificates from 27 states of the United States[J].Occup Environ Med,2003,60(2): 122-129.
[3] Rees D,Murray J.Silica,silicosis and tuberculosis[J].Int J Tuberc Lung Dis,2007,11(5): 474-484.
[4] 李德鸿．加强预防措施研究 强化管理监督机制 为实现消除尘肺病而努力[J]．中华劳动卫生职业病杂志，2001，19(1)：1-2．
[5] Becklake M R.The mineral dust diseases[J].Tuber Lung Dis,1992,73(1): 13-20.
[6] Nadif R,Jedlicka A,Mintz M,et al.Effect of TNF and LTA polymorphisms on biological markers of response to oxidative stimuli in coal miners: a model of gene-environment interaction.Tumour necrosis factor and lymphotoxin alpha[J].J Med Genet,2003,40(2): 96-103.
[7] Risch N,Merikangas K.The future of genetic studies of complex human diseases[J].Science,1996,273(5281): 1516-1517.
[8] McCarthy J J,Hilfiker R.The use of single-nucleotide polymorphism maps in pharmacogenomics[J].Nat Biotechnol,2000,18(5): 505-508.
[9] McCanlies E,Landsittel D P,Yucesoy B,et al.Significance of genetic information in risk assessment and individual classification using silicosis as a case model[J].Ann Occup Hyg,2002,46(4): 375-381.
[10] Koskinen H,Tiilikainen A,Nordman H.Increased prevalence of HLA-Aw19 and of the phenogroup Aw19,B18 in advanced silicosis[J].Chest,1983,83(6): 848-852.
[11] Corbett E L,Mozzato-Chamay N,Butterworth A E,et al.Polymorphisms in the manor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners[J].Am J Respir Crit Care Med,2002,165(5): 690-693.
[12] Yucesoy B,Vallyathan V,Landsittel D P,et al.Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis[J].Toxicol Appl Pharmacol,2001,172(1): 75-82.
[13] 范雪云，李娟，王欣荣，等．转化生长因子-β(-509、+869、+915)位点基因多态性与尘肺易感性[J]．中华劳动卫生职业病杂志，2007，25(1)：1-4．
[14] 范雪云，王欣荣，李翠兰，等．白细胞介素-6基因多态性与尘肺易感性的病例对照研究[J]．中国职业医学，2007，34(3)：199-201，204．
[15] 范雪云，闫兆凤，闫进德，等．白细胞介素-1基因多态性与尘肺易感性的关系[J]．中华劳动卫生职业病杂志，2006，24(9)：526-530．
[16] 李霖，余晨，齐放，等．肿瘤坏死因子-a及其Ⅱ型受体基因多态性与矽肺[J]．中华劳动卫生职业病杂志，2004，22(5)：323-326．
[17] 王德军，杨跃林，夏庆杰，等．肿瘤坏死因子α基因多态性与矽肺遗传易感性的研究[J]．四川大学学报：医学版，2005，36(5)：679-682，712．
[18] 邹昌淇，邵强．为全球消除矽肺规划作出贡献[J]．中华劳动卫生职业病杂志，1999，17(1)：2-4．
[19] Wang X R,Christiani D C.Occupational lung disease in China[J].Int J Occup Environ Health,2003,9(4): 320-325.
[20] 李克，郑继烈．呼吸性矽尘容许限值的研究：有色金属矿山工人粉尘暴露与尘肺…[J]．中国工业医学杂志，1994，7(2)：68-71，93．
[21] Muir D C,Julian J A,Shannon H S,等.Silica exposure and silicosis among Ontario hardrock miners: Ⅲ.Analysis and risk estimates[J].Am J Ind Med,1989,16(1): 29-43.
[22] Hnizdo E,Sluis-Cremer G K.Risk of silicosis in a cohort of white South African gold miners[J].Am J Ind Med,1993,24(4): 447-457.
[23] 陈卫红，傅长汉．锡矿工人接尘与矽肺危险度评价[J]．中华劳动卫生职业病杂志， 1999，17(3)：131-134．
[24] U.S.Department of Health and Human Services.The health consequences of smoking: 25 years of progress-A report of the U.S.Surgeon General [J].1989.
[25] 孟昭阁，张国忱，邢国长．矿山矽肺与肺结核防治[J]．1985：1-150．
[26] 王簃兰，刚葆琪．现代劳动卫生学[J]．1994：103．
[27] Gamble J F,Hessel P A,Nicolich M.Relationship between silicosis and lung function[J].Scand J Work Environ Health,2004,30(1): 5-20.
[28] 张培元．为什么制定肺结核和非结核分支杆菌病诊治指南[J]．中华结核和呼吸杂志， 2001，24(2)：69-69．
[29] Hnizdo E,Churchyard G,Dowdeswel R.Lung function prediction equations derived from healthy South African gold miners[J].Occup Environ Med,2000,57(10): 698-705.
[30] 何仅瀛，林江涛．现代呼吸疾病诊断学[J]．2002：229-244．
[31] Davies P,Grange J.The genetics of host resistance and susceptibility to tuberculosis[J].Ann N Y Acad Sci,2001,953: 151-156.
[32] Gozal E,Ortiz L A,Zou X,et al.Silica-induced apoptosis in murine macrophage: involvement of tumor necrosis factor-alpha and nuclear factor-kappaB activation[J].Am J Respir Cell Mol Biol,2002,27(1): 91-98.
[33] Cowie R L.The epidemiology of tuberculosis in gold miners with silicosis[J].Am J Respir Crit Care Med,1994,150(5 Pt 1): 1460-1462.
[34] 何广学．现代结核病控制措施下结核病传染参数的研究[J]．中国防痨杂志，2002，24(6)：340-342．
[35] Wang X,Yano E.Pulmonary dysfunction in silica-exposed workers: a relationship to radiographic signs of silicosis and emphysema[J].Am J Ind Med,1999,36(2): 299-306.
[36] 胡克，陈喜兰，杨炯弥．弥漫性肺疾病临床诊断学[J]．2003：483-486．
[37] Srivastava K D,Rom W N,Jagirdar J,et al.Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice[J].Am J Respir Crit Care Med,2002,165(4): 527-533.
[38] Kang J L,Lee K,Castranova V.Nitric oxide up-regulates DNA-binding activity of nuclear factor-kappaB in macrophages stimulated with silica and inflammatory stimulants[J].Mol Cell Biochem,2000,215(1-2): 1-9.
[39] Kang J L,Pack I S,Lee H S,et al.Enhancelnent of nuclear factor-kappaB activation and protein tyrosine phosphorylation by a tyrosine phosphatase inhibitor,pervanadate,involves reactive oxygen species in silica-stimulated macrophages[J].Toxicology,2000,151(1-3): 81-89.
[40] Wonnhoudt L W,Commandeur J N,Vermeulen N P.Genetic polymorphisms of human N-acetyltransferase,cytochrome P450,glutathione-S-transferase,and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity[J].Crit Rev Toxicol,1999,29(1): 59-124.
[41] Sachidanandam R,Weissman D,Schmidt S C,et al.A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms[J].Nature,2001,409(6822): 928-933.
[42] Rimal B,Greenberg A K,Rom W N.Basic pathogenetic mechanisms in silicosis: current understanding[J].Curr Opin Pulm Med,2005,11 (2): 169-173.
[43] Jagirdar J,Begin R,Dufresne A,et al.Transforming growth factor-beta (TGF-beta) in silicosis[J].Am J Respir Crit Care Med,1996,154(4 Pt 1): 1076-1081.
[44] Barbarin V,Arras M,Misson P,et al.Characterization of the effect of interleukin-10 on silica-induced lung fibrosis in mice[J].Am J Respir Cell Mol Biol,2004,31(I): 78-85.
[45] Barbarin V,Xing Z,Delos M,et al.Puhnonary overexpression of IL-10 augments lung fibrosis and Th2 responses induced by silica particles[J].Am J Physiol Lung Cell Mol Physiol,2005,288(5): L841-848.
[46] Chen Y,Chen J,Dong J,et al.Antifibrotic effect of interferon gamma in silicosis model of rat[J].Toxicol Lett,2005,155(3): 353-360.
[47] Baroni T,Bodo M,D'Alessandro A,et al.Silica and its antagonistic effects on transforming growth factor-beta in lung fibroblast extracellular matrix production[J].J Investig Med,2001,49(2): 146-156.
[48] 陈莹，董静，陈杰．γ-干扰素对矽肺大鼠肿脏向介素-4和转化生长因子-β1蛋白表达的影响[J]．中华劳动卫生职业病杂志，2004，22(5)：350-353．
[49] Struhar D J,Harbeck R J,Gegen N,et al.Increased expression of class Ⅱ antigens of the major histocompatibility complex on alveolar macrophages and alveolar type Ⅱ cells and interleukin-1 (IL-1) secretion from alveolar macrophages in an animal model of silicosis[J].Clin Exp Immunol,1989,77(2): 281-284.
[50] Driscoll K E,Lindenschmidt R C,Maurer J K,et al.Pulmonary response to silica or titanium dioxide: inflammatory cells,alveolar macrophage-derived cytokines,and histopathology[J].Am J Respir Cell Mol Biol,1990,2(4): 381-390.
[51] Mohr C,Gemsa D,Graebner C,et al.Systemic macrophage stimulation in rats with silicosis: enhanced release of tumor necrosis factor-alpha from alveolar and peritoneal macrophages[J].Am J Respir Cell Mol Biol,1991,5(4): 395-402.
[52] Davis G S,Pfeiffer L M,Hemenway D R.Persistent overexpression of interleukin-lbeta and tumor necrosis factor-alpha in murine silicosis[J].J Environ Pathol Toxicol Oncol,1998,17(2): 99-114.
[53] Orfila C,Lepert J C,Gossart S,et al.Immunocytochemical characterization of lung macrophage surface phenotypes and expression of cytokines in acute experimental silicosis in mice[J].Histochem J,1998,30(12): 857-867.
[54] Piguet P F,Collart M A,Grau G E,et al.Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis [J].Nature,1990,344(6263): 245-247.
[55] Gossart S,Cambon C,Orfila C,et al.Reactive oxygen intermediates as regulators of TNF-alpha production in rat lung inflammation induced by silica[J].J Immunol,1996,156(4): 1540-1548.
[56] Fubini B,Hubbard A.Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis[J].Free Radic Biol Med,2003,34(12): 1507-1516.
[57] Gosset P,Lassalle P,Vanhee D,et al.Production of tumor necrosis factor-alpha and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust[J].Am J Respir Cell Mol Biol,1991,5(5): 431-436.
[58] Vanhee D,Gosset P,Boitelle A,et al.Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis[J].Eur Respir J,1995,8(5): 834-842.
[59] 冯国贤，南培宏．早期矽肺患者支气管肺泡灌洗液中生物标志物的研究[J]．中华劳动卫生职业病杂志，2000，18(4): 226-228.
[60] Zhang Y,Lee T C,Guillemin B,et al.Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure[J].J Immunol,1993,150(9): 4188-4196.
[61] Schmidt J A,Oliver C N,Lepe-Zuniga J L,et al.Silica-stimulated monocytes release fibroblast proliferation factors identical to interleukin 1.A potential role for interleukin 1 in the pathogenesis of silicosis[J].J Clin Invest,1984,73(5): 1462-1472.
[62] Savici D,He B,Geist L J,et al.Silica increases tumor necrosis factor (TNF) production,in part,by upregulating the TNF promoter[J].Exp Lung Res,1994,20(6): 613-625.
[63] 姬文婕，杨磊，王正伦，等．染矽尘小鼠肺组织中转化生长因子β1表达的逆转录聚合酶链反应检测[J]．中华劳动卫生职业病杂志，2003，21(3)：185-187．
[64] Olbruck H,Seemayer N H,Voss B,et al.Supernatants from quartz dust treated human macrophages stimulate cell proliferation of different human lung cells as well as collagen-synthesis of human diploid lung fibroblasts in vitro[J].Toxicology Letters,1998,96-97: 85-95.
[65] Denis M.Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis[J].Immunology,1994,82(4): 584-590.
[66] 姬文婕，程东军，杨磊．矽肺及矽尘作业工人生物监测指标的探讨[J]．中华劳动卫生职业病杂志，2005，23(3)：217-218．
[67] Huaux F,Louahed J,Hudspith B,et al.Role of interleukin-10 in the lung response to silica in mice[J].Am J Respir Cell Mol Biol,1998,18(1): 51-59.
[68] Ulloa L,Doody J,Massague J.Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway[J].Nature,1999,397(6721): 710-713.
[69] Ghosh A K,Yuan W,Mori Y,et al.Antagonistic regulation of type Ⅰ collagen gene expression by interferon-gamma and transforming growth factor-beta.Integration at the level of p300/CBP transcriptional coactivators[J].J Biol Chem,2001,276(14): 11041-11048.
[70] Abraham L J,Kroeger K M.Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease[J].J Leukoc Biol,1999,66(4): 562-566.
[71] Witte J S,Palmer L J,O'Connor R D,et al.Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma[J].Eur J Hum Genet,2002,10(1): 82-85.
[72] Schaaf B M,Seitzer U,Pravica V,et al.Tumor necrosis factor-alpha -308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer's lung patients[J].Am J Respir Crit Care Med,2001,163(2): 379-382.
[73] 王博蔚．肿瘤坏死因子基因多态性与疾病[J]．国外医学：免疫学分册，2000，23(2)：89-92．
[74] 徐旭雯，鲁猛厚．肿瘤坏死因子基因多态性与感染性疾病[J]．国外医学：生理病理科学与临床分册，2003，23(6)：653-656．
[75] 朱丽红，栾庆先．肿瘤坏死因子基因多态性与牙周炎[J]．国外医学：口腔医学分册，2005，32(2)：99-101．
[76] 周国胜，吴正祥．炎症性肠病与肿瘤坏死因子基因多态性的研究进展[J]．世界华人消化杂志，2008，16(21)：2390-2394．
[77] 曹倩，高敏，周刚，等．肿瘤坏死因子基因多态性与溃疡性结肠炎相关性研究[J]．中华消化杂志，2006，26(7)：460-463．
[78] Ates O,Hatemi G,Hamuryudan V,et al.Tumor necrosis factor-alpha and interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients[J].Clin Rheumatol,2008,27(10): 1243-1248.
[79] Whyte M,Hubbard R,Meliconi R,et al.Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms[J].Am J Respir Crit Care Med,2000,162(2 Pt 1): 755-758.
[80] 孙智霞，姚三巧，范雪云．肿瘤坏死因子基因多态性与纤维化性疾病的相关性[J]．中国职业医学，2004，31(5)：57-58．
[81] Libura J,Bettens F,Radkowski A,et al.Risk of chemotherapy-induced pulmonary fibrosis is associated with polymorphic tumour necrosis factor-a2 gene[J].Eur Respir J,2002,19(5): 912-918.
[82] Riha R L,Yang I A,Rabnott G C,et al.Cytokine gene polymorphisms in idiopathic pulmonary fibrosis[J].Intern Med J,2004,34(3): 126-129.
[83] Zhai R,Jetten M,Schins R P,et al.Polymorphisms in the promoter of the tumor necrosis factor-alpha gene in coal miners[J].Am J Ind Med,1998,34(4): 318-324.
[84] Kim K A,Cho Y Y,Cho J S,et al.Tumor necrosis factor-alpha gene promoter polylnorphism in coal workers' pneumoconiosis[J].Mol Cell Biochem,2002,234-235(1-2): 205-209.
[85] Yucesoy B,Vallyathan V,Landsittel D P,et al.Cytokine polymorphisms in silicosis and other pneumoconioses[J].Mol Cell Biochem,2002,234-235(1-2): 219-224.
[86] Majetschak M,Flohe S,Obertacke U,et al.Relation of a TNF gene polymorphism to severe sepsis in trauma patients[J].Ann Surg,1999,230(2): 207-214.
[87] Yamaguchi E,Itoh A,Hizawa N,et al.The gene polymorphism of tumor necrosis factor-beta,but not that of tumor necrosis factor-alpha,is associated with the prognosis of sarcoidosis[J].Chest,2001,119(3): 753-761.
[88] Bettinotti M P,Hartung K,Deicher H,et al.Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythelnatosus: TNFB-MHC haplotypes[J].Immunogenetics,1993,37(6): 449-454.
[89] Lu L Y,Cheng H H,Sung P K,et al.Tumor necrosis factor-beta +252A polymorphism is associated with systemic lupus erythematosus in Taiwan[J].J Fonnos Med Assoc,2005,104(8): 563-570.
[90] Nonomura N,Tokizane T,Nakayama M,et al.Possible correlation between polymorphism in the tumor necrosis factor-beta gene and the clinicopathological features of bladder cancer in Japanese patients[J].Int J Urol,2006,13(7): 971-976.
[91] Shimura T,Hagihara M,Takebe K,et al.The study of tumor necrosis factor beta gene polymorphism in lung cancer patients[J].Cancer,1994,73(4): 1184-1188.
[92] Grainger D J,Heathcote K,Chiano M,et al.Genetic control of the circulating concentration of transforming growth factor type betal[J].Hum Mol Genet,1999,8(1): 93-97.
[93] Yamada Y,Miyauchi A,Goto J,et al.Association of a polymorphism of the transforming growth factor-betal gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women[J].J Bone Miner Res,1998,13(10): 1569-1576.
[94] Awad M R,El-Gamel A,Hasleton P,et al.Genotypic variation in the transforming growth factor-betal gene: association with transforming growth factor-betal production,fibrotic lung disease,and graft fibrosis after lung transplantation[J].Transplantation,1998,66(8): 1014-1020.
[95] El-Gamel A,Awad M R,Hasleton P S,et al.Transforming growth factor-beta (TGF-betal) genotype and lung allograft fibrosis[J].J Heart Lung Transplant,1999,18(6): 517-523.
[96] Xaubet A,Marin-Arguedas A,Lario S,et al.Transforming growth factor-betal gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med.2003.168(4): 431-435.
[97] 吕铁明，谭建明，等．细胞因子基因多态性与细胞因子水平关系的研究[J]．中华器官移植杂志，2002，23(5)：266-268．
[98] 刘庆华，辛洪涛．转化生长因子-β与肺纤维化[J]．国外医学：内科学分册，2002，29(8)：339-340，355．
[99] 姚武，郝长付，吴逸明，等．转化生长因子β1血清浓度及基因多态性与煤工尘肺的关系[J]．中国职业医学，2006，33(4)：265-268．
[100] 姚武，郝长付，王娜，等．转化生长因子β1基因多态性对煤工尘肺遗传易感性的影响[J]．现代预防医学，2006，33(10)：1875-1877．
[101] Asadullah K,Sterry W,Volk H D.Interleukin-10 therapy--review of a new approach[J].Pharmacol Rev,2003,55(2): 241-269.
[102] Turner D M,Williams D M,Sankaran D,et al.An investigation of polymorphism in the interleukin- 10 gene promoter[J].Eur J Immunogenet,1997,24(1): 1-8.
[103] Kurreeman F A,Schonkeren J J,Heijmans B T,et al.Transcription of the ILl0 gene reveals allele-specific regulation at the mRNA level[J].Hum Mol Genet,2004,13(16): 1755-1762.
[104] Edwards-Smith C J,Jonsson J R,Purdie D M,et al.Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa[J].Hepatology,1999,30(2): 526-530.
[105] Henri S,Chevillard C,Mergani A,et al.Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease[J].J Immunol,2002,169(2): 929-936.
[106] Pastor I J,Laso F J,Romero A,et al.-238 G＞A polymorphism of tumor necrosis factor alpha gene (TNFA) is associated with alcoholic liver cirrhosis in alcoholic Spanish men[J].Alcohol Clin Exp Res,2005,29(11): 1928-1931.
[107] Warzocha K,Ribeiro P,Bienvenu J,et al.Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome[J].Blood,1998,91(10): 3574-3581.
[108] Um J Y,Moon K S,Lee K M,et al.Association of interleukin-1 alpha gene polymorphism with cerebral infarction[J].Brain Res Mol Brain Res,2003,115(1): 50-54.
[109] Lu W,Pan K,Zhang L,et al.Genetic polymorphisms of interleukin (IL)-1B,IL-1RN,IL-8,IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population[J].Carcinogenesis,2005,26(3): 631-636.
[110] di Giovine F S,Takhsh E,Blakemore A I,et al.Single base polymorphism at -511 in the human intefleukin-1 beta gene (IL1 beta)[J].Hum Mol Genet,1992,1(6): 450.
[111] Pociot F,Molvig J,Wogensen L,et al.A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro[J].Eur J Clin Invest,1992,22(6): 396-402.
[112] Tarlow J K,Blakemore A I,Lennard A,et al.Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat[J].Hum Genet,1993,91(4): 403-404.
[113] Caserta T M,Knisley A A,Tan F K,et al.Genotypic analysis of the TGF beta-509 allele in patients with systemic lupus erythematosus and Sjogren's syndrome[J].Ann Genet,2004,47(4): 359-363.
[114] Amani D,Dehaghani A S,Zolghadri J,et al.Lack of association between the TGF-beta1 gene polymorphisms and recurrent spontaneous abortion[J]. J Reprod Immunol, 2005,68(1-2): 91-103.
[115] Ma S L, Tang N L, Lam L C, et al. The association between promoter polymorphism of the interleukin-10 gene and Alzheimer's disease[J]. Neurobiol Aging, 2005, 26(7):1005-1010.
[116] Chang Y H, Huang C N, Wu C Y, et al. Association of interleukin-10 A-592C and T-819C polymorphisms with type 2 diabetes mellitus[J]. Hum Immunol, 2005, 66(12):1258-1263.
[117] Zambon C F, Basso D, Navaglia F, et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome[J].Cytokine, 2005, 29(4): 141-152.
[118] 张忠彬,朱人,夏昭林.应用CRS—RFLP 技术检测 hOGGlc.326 位点的单核苷酸多态性[J]. 中国工业医学杂志,2004, 17(5): 293-296.
[119] Shi Y Y, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci[J].Cell Res, 2005, 15(2): 97-98.
[120] Machado J C, Pharoah P, Sousa S, et al. Interleukin lB and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma[J].Gastroenterology, 2001, 121(4): 823-829.
[121] Ding M, Chen F, Shi X, et al. Diseases caused by silica: mechanisms of injury and disease development[J]. Int Immunophannacol, 2002, 2(2-3): 173-182.
[122] Stuber F, Petersen M, Bokelmann F, et al. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis[J]. Crit Care Med, 1996, 24(3): 381-384.
[123] Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans[J]. Clin Exp Immunol, 1998, 113(3): 401-406.
[124] Bouma G, Crusius J B, Oudkerk Pool M, et al. Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease[J]. Scand J Immunol, 1996, 43(4):456-463.
[125] Wilson A G, di Giovine F S, Blakemore A I, et al. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by Ncol restriction of PCR product[J]. Hum Mol Genet, 1992, 1(5): 353.
[126] Hajeer A H, Hutchinson I V. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease[J]. Hum Immunol, 2001, 62(11): 1191-1199.
[127] Brinkman B M, Giphart M J, Verhoef A, et al. Tumor necrosis factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome[J].Hum Immunol, 1994, 41(4): 259-266.
[128] Brinkman B M, Kaijzel E L, Huizinga T W, et al. Detection of a C-insertion polymorphism within the human tumor necrosis factor alpha (TNFA) gene[J]. Hum Genet,1995, 96(4): 493.
[129] D'Alfonso S, Richiardi P M. A polymorphic variation in a putative regulation box of the TNFA promoter region[J]. Immunogenetics, 1994,39(2): 150-154.
[130] Hamann A, Mantzoros C, Vidal-Puig A, et al. Genetic variability in the TNF-alpha promoter is not associated with type Ⅱ diabetes mellitus (NIDDM)[J]. Biochem Biophys Res Commun, 1995,211(3): 833-839.
[131] Higuchi T, Seki N, Kamizono S, et al. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese[J]. Tissue Antigens, 1998,51(6): 605-612.
[132] Uglialoro A M, Turbay D, Pesavento P A, et al. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter[J].Tissue Antigens, 1998, 52(4): 359-367.
[133] Zimmerman P A, Guderian R H, Nutman T B. A new TNFA promoter allele identified in South American Blacks[J]. Immunogenetics, 1996, 44(6): 485-486.
[134] Bayley J P, de Rooij H, van den Elsen P J, et al. Functional analysis of linker-scan mutants spanning the -376, -308, -244, and -238 polymorphic sites of the TNF-alpha promoter[J].Cytokine,2001,14(6): 316-323.
[135] Frigerio S,Ciusani E,Pozzi A,et al.Tumor necrosis factor microsatellite polymorphisms in Italian glioblastoma patients[J].Cancer Genet Cytogenet,1999,109(2): 172-174.
[136] Kroeger K M,Carville K S,Abraham L J.The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription[J].Mol Immunol,1997,34(5): 391-399.
[137] Messer G,Spengler U,Jung M C,et al.Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production[J].J Exp Med,1991,173(1): 209-219.
[138] 王德军，杨跃林，夏庆杰，等．肿瘤坏死因子α基因多态性与矽肺的相关性[J]．职业卫生与病伤，2005，20(1)：1-4．
[139] Meenagh A,Williams F,Ross O A,et al.Frequency of cytokine polymorphisms in populations from western Europe,Africa,Asia,the Middle East and South America[J].Hum Immunol,2002,63(11): 1055-1061.
[140] 陈雅萍，宋志芳．脂类介质、细胞因子与矽肺炎症、纤维化[J]．职业卫生与病伤，1999，14(1)：48-51．
[141] Kolb M,Margetts P J,Anthony D C,et al.Transient expression of IL-lbeta induces acute lung injury and chronic repair leading to pulmonary fibrosis[J].J Clin Invest,2001,107(12): 1529-1536.
[142] Hulkkonen J,Laippala P,Hurme M.A rare allele combination of the interleukin-1 gene complex is associated with high interleukin-1 beta plasma levels in healthy individuals[J].Eur Cytokine Netw,2000,11(2): 251-255.
[143] El-Omar E M,Carrington M,Chow W H,et al.Interleukin-1 polymorphisms associated with increased risk of gastric cancer[J].Nature,2000,404(6776): 398-402.
[144] Hamajima N,Matsuo K,Saito T,et al.Interleukin 1 polymorphisms,lifestyle factors,and Helicobacter pylori infection[J].Jpn J Cancer Res,2001,92(4): 383-389.
[145] Chang Y W,Jang J Y,Kim N H,et al.Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer[J].Int J Cancer,2005,114(3): 465-471.
[146] Takamatsu M,Yamauchi M,Maezawa Y,et al.Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients[J].Am J Gastroenterol,2000,95(5): 1305-1311.
[147] Gaeta G,De Michele M,Cuomo S,et al.Arterial abnormalities in the offspring of patients with premature myocardial infarction[J].N Engl J Med,2000,343(12): 840-846.
[148] Wood N A,Thomson S C,Smith R M,et al.Identification of human TGF-betal signal (leader) sequence polymorphisms by PCR-RFLP[J].J Immunol Methods,2000,234(1-2): 117-122.
[149] Zhou X,Tan F K,Stivers D N,et al.Microsatellites and intragenic polymorphisms of transforming growth factor beta and platelet-derived growth factor and their receptor genes in Native Americans with systemic sclerosis (scleroderma): a preliminary analysis showing no genetic association[J].Arthritis Rheum,2000,43(5): 1068-1073.
[150] Bayat A,Bock O,Mrowietz U,et al.Genetic susceptibility to keloid disease and hypertrophic scarring: transforming growth factor betal common polymorphisms and plasma levels[J].Plast Reconstr Surg,2003,111(2): 535-543; discussion 544-536.
[151] Yang Y H,Lai H J,Kao C K,et al.The association between transforming growth factor-beta gene promoter C-509T polymorphism and Chinese children with Henoch-Schonlein purpura[J].Pediatr Nephrol,2004,19(9): 972-975.
[152] Yokota M,Ichihara S,Lin T L,et al.Association of a T29--＞C polymorphism of the transforming growth factor-betal gene with genetic susceptibility to myocardial infarction in Japanese[J].Circulation,2000,101 (24): 2783-2787.
[153] Arkwright P D,Laurie S,Super M,et al.TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis[J].Thorax,2000,55(6): 459-462.
[154] Gewaltig J,Mangasser-Stephan K,Gartung C,et al.Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis[J].Clin Chim Acta,2002,316(1-2): 83-94.
[155] Eskdale J,Kube D,Tesch H,et al.Mapping of the human IL10 gene and further characterization of the 5'flanking sequence[J].Immunogenetics,1997,46(2): 120-128.
[156] Lazarus M,Hajeer A H,Turner D,et al.Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus[J].J Rheumatol,1997,24(12): 2314-2317.
[157] Tagore A,Gonsalkorale W M,Pravica V,et al.Interleukin-10 (IL-10) genotypes in inflammatory bowel disease[J].Tissue Antigens,1999,54(4): 386-390.
[158] Faupel-Badger J M,Kidd L C,Albanes D,et al.Association of IL-10 polymorphisms with prostate cancer risk and grade of disease[J].Cancer Causes Control,2008,19(2): 119-124.
[159] Lech-Maranda E,Baseggio L,Charlot C,et al.Genetic polymorphisms in the proximal IL-10 promoter and susceptibility to non-Hodgkin lymphoma[J].Leuk Lymphoma,2007,48(11): 2235-2238.
[160] Castro-Santos P,Suarez A,Lopez-Rivas L,et al.TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease.Association of-1082 AA low producer IL-10 genotype with steroid dependency[J].Am J Gastroenterol,2006,101(5): 1039-1047.
[161] Hajeer A H,Lazarus M,Turner D,et al.IL-10 gene promoter polymorphisms in rheumatoid arthritis[J].Scand J Rheumatol,1998,27(2): 142-145.
[162] Eskdale J,Wordsworth P,Bowman S,et al.Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus[J].Tissue Antigens,1997,49(6): 635-639.
[163] 张平交，李艳，杨相会．白细胞介素10基因启动子区多态性与乙型肝炎病毒感染预后的关联研究[J]．中华医学遗传学杂志，2006，23(4)：410-414．
[164] Hulkkonen J,Pertovaara M,Antonen J,et al.Genetic association between interleukin-10 promoter region polymorphisms and primary Sjogren's syndrome[J].Arthritis Rheum,2001,44(1): 176-179.
[165] Kusumoto K,Uto H,Hayashi K,et al.Interleukin-10 or tumor necrosis factor-alpha polymorphisms and the natural course of hepatitis C virus infection in a hyperendemic area of Japan[J].Cytokine,2006,34(1-2): 24-31.
[166] Chevillard C,Henri S,Stefani F,et al.Two new polymorphisms in the human interferon gamma (IFN-gamma) promoter[J].Eur J Immunogenet,2002,29(1): 53-56.
[167] Henri S,Stefani F,Parzy D,et al.Description of three new polymorphisms in the intronic and 3'UTR regions of the human interferon gamma gene[J].Genes hnmun,2002,3(1): 1-4.
[168] Pravica V,Perrey C,Stevens A,et al.A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production[J].Hum Immunol,2000,61(9): 863-866.
[169] 李志方，卢健红，李景柔，等．Ifn-γ基因多态性与小儿哮喘的相关性[J]．中国优生与遗传杂志，2006，14(9)：22-23．
[170] 张平安，吴健民，李艳．干扰素γ基因内含子1+874位点多态性与乙型肝炎病毒感染关系的研究[J]．中华流行病学杂志，2006，27(1)：41-43．
[171] Ding S,Li L,Zhu X.Polymorphism of the interferon-gamma gene and risk of tuberculosis in a southeastern Chinese population[J].Hum Immunol,2008,69(2): 129-133.
[172] 朱启镕，俞慧，顾绍庆，等．干扰素γ和肿瘤坏死因子α基因单核苷酸多态性与宫内乙肝病毒感染易感性研究[J]．临床儿科杂志，2005．23(7)：446-449．
[173] Hessel P A,Gamble J F,Nicolich M.Relationship between silicosis and smoking[J].Scand J Work Environ Health,2003,29(5): 329-336.
[174] Castranova V,Porter D,Millecchia L,et al.Effect of inhaled crystalline silica in a rat model: time course of pulmonary reactions[J].Mol Cell Biochem,2002,234-235(1-2): 177-184.
[175] Porter D W,Ye J,Ma J,et al.Time course of puhnonary response of rats to inhalation of crystalline silica: NF-kappa B activation,inflammation,cytokine production,and damage[J].Inhal Toxicol,2002,14(4): 349-367.
[176] Hubbard A K,Timblin C R,Shukla A,et al.Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice[J].Am J Physiol Lung Cell Mol Physiol,2002,282(5): L968-975.
[177] Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B[J].Annu Rev Cell Biol, 1994, 10: 405-455.
[178] 叶进燕,陈少贤.核因子 κ b 与肺部疾病[J]. 国外医学:内科学分册, 2004,31(1):29-33.
[179] Baldwin A S, Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights[J].Annu Rev Immunol, 1996, 14: 649-683.
[180] May M J, Ghosh S. Signal transduction through NF-kappa B[J]. Immunol Today, 1998,19(2): 80-88.
[181] Karban A S, Okazaki T, Panhuysen C I, et al. Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis[J]. Hum Mol Genet, 2004,13(1): 35-45.
[182] Conne B, Stutz A, Vassalli J D. The 3' untranslated region of messenger RNA: A molecular ‘hotspot' for pathology?[J]. Nat Med, 2000, 6(6): 637-641.
[183] Szamosi T, Lakatos P L, Szilvasi A, et al. The 3'UTR NFKBIA variant is associated with extensive colitis in Hungarian IBD patients[J]. Dig Dis Sci, 2009, 54(2): 351-359.
[184] Hong J, Leung E, Fraser A G, et al. Polymorphisms in NFKBIA and ICAM-1 genes in New Zealand Caucasian Crohn's disease patients[J]. J Gastroenterol Hepatol, 2007,22(10): 1666-1670.
[185] Gao J, Pfeifer D, He L J, et al. Association of NFKBIA polymorphism with colorectal cancer risk and prognosis in Swedish and Chinese populations[J]. Scand J Gastroenterol,2007, 42(3): 345-350.
[186] Klein W, Tromm A, Folwaczny C, et al. A polymorphism of the NFKBIA gene is associated with Crohn's disease patients lacking a predisposing allele of the CARD15 gene[J]. Int J Colorectal Dis, 2004, 19(2): 153-156.
[187] Kim L H, Shin H D, Park B L, et al. Identification of variants in NFKBIA and association analysis with hepatocellular carcinoma risk among chronic HBV patients[J]. Hum Mutat,2003, 21(6): 652-653.
[188] Parker K M, Ma M H, Manyak S, et al. Identification of polymorphisms of the IkappaBalpha gene associated with an increased risk of multiple myeloma[J]. Cancer Genet Cytogenet, 2002, 137(1): 43-48.
[189] Leshinsky-Silver E, Karban A, Cohen S, et al. Lack of association of the 3'-UTR polymorphism in the NFKBIA gene with Crohn's disease in an Israeli cohort[J]. Int J Colorectal Dis, 2007, 22(9): 1021-1025.
[190] Curran J E, Weinstein S R, Griffiths L R. Polymorphic variants of NFKB1 and its inhibitory protein NFKBIA, and their involvement in sporadic breast cancer[J]. Cancer Lett, 2002, 188(1-2): 103-107.
[191] Lin S C, Liu C J, Yeh W I, et al. Functional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewers[J]. Cancer Lett, 2006,243(1): 47-54.
[192] Mossman B T, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis[J].Am J Respir Crit Care Med, 1998, 157(5 Pt 1): 1666-1680.
[193] Hamilton R F, Jr., Pfau J C, Marshall G D, et al. Silica and PM1648 modify human alveolar macrophage antigen-presenting cell activity in vitro[J]. J Environ Pathol Toxicol Oncol, 2001, 20 Suppl 1: 75-84.
[194] Yamamoto Y, Gaynor R B. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer[J]. J Clin Invest, 2001,107(2): 13(?)-142.
[195] Senftleben U, Cao Y, Xiao G, et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway[J]. Science, 2001, 293(5534): 1495-1499.
[196] Jungnickel B, Staratschek-Jox A, Brauninger A, et al. Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma[J]. J Exp Med, 2000,191(2): 395-402.
[197] Beg A A, Sha W C, Bronson R T, et al. Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice[J]. Genes Dev,1995, 9(22): 2736-2746.
[198] Hochwald S N, Lind D S, Malaty J, et al. Antineoplastic therapy in colorectal cancer through proteasome inhibition[J]. Am Surg, 2003, 69(1): 15-23.
[199] Scaife C L, Kuang J, Wills J C, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis[J]. Cancer Res,2002, 62(23): 6870-6878.
[200] Bonn M E, van Bodegraven A A, Mulder C J, et al. A NFKB1 promoter polymorphism is involved in susceptibility to ulcerative colitis[J]. Int J Immunogenet, 2005, 32(6):401-405.
[201] Oliver J, Gomez-Garcia M, Paco L, et al. A functional polymorphism of the NFKB1 promoter is not associated with ulcerative colitis in a Spanish population[J]. Inflamm Bowel Dis, 2005, 11(6): 576-579.
[202] Kurylowicz A, Hiromatsu Y, Jurecka-Lubieniecka B, et al. Association of NFKB1 -94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease[J]. Genes Immun, 2007, 8(7): 532-538.
[203] Lewander A, Butchi A K, Gao J, et al. Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations[J]. Scand J Gastroenterol, 2007, 42(11): 1332-1338.
[204] Riemann K, Becker L, Struwe H, et al. Insertion/deletion polymorphism in the promoter of NFKB1 as a potential molecular marker for the risk of recurrence in superficial bladder cancer[J]. Int J Clin Pharmacol Ther, 2007, 45(8): 423-430.
[205] Lo S S, Chen J H, Wu C W, et al. Functional polymorphism of NFKB1 promoter may correlate to the susceptibility of gastric cancer in aged patients[J]. Surgery, 2009, 145(3):280-285.
[206] Zhou B, Rao L, Li Y, et al. A functional insertion/deletion polymorphism in the promoter region of NFKB1 gene increases susceptibility for nasopharyngeal carcinoma[J]. Cancer Lett, 2009, 275(1): 72-76.
[207] Bu H, Rosdahl I, Sun X F, et al. Importance of polymorphisms in NF-kappaBl and NF-kappaBIalpha genes for melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients[J]. J Cancer Res Clin Oncol, 2007, 133(11):859-866.
[208] Mirza M M, Fisher S A, Onnie C, et al. No association of the NFKB1 promoter polymorphism with ulcerative colitis in a British case control cohort[J]. Gut, 2005, 54(8):1205-1206.
[209] Glas J, Torok H P, Tonenchi L, et al. Role of the NFKB1 -94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes[J]. Inflamm Bowel Dis, 2006, 12(7):606-611.
[210] Kosoy R, Concannon P. Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes[J]. Genes Immun, 2005, 6(3): 231-235.
[211] Orozco G, Sanchez E, Collado M D, et al. Analysis of the functional NFKB1 promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus[J]. Tissue Antigens, 2005, 65(2): 183-186.
[212] Martin J, Perez-Annengol C, Miranda-Filloy J A, et al. Lack of association of a functional -94ins/delATTG NFKB1 promoter polymorphism with susceptibility and clinical expression of biopsy-proven giant cell arteritis in northwest Spain[J]. J Rheumatol, 2006,33(2): 285-288.
[213] Rueda B, Nunez C, Lopez-Nevot M A, et al. Functional polymorphism of the NFKB1 gene promoter is not relevant in predisposition to celiac disease[J]. Scand J Gastroenterol,2006, 41(4): 420-423.
[214] Riemann K, Becker L, Struwe H, et al. No association of the NFKB1 insertion/deletion promoter polymorphism with survival in colorectal and renal cell carcinoma as well as disease progression in B-cell chronic lymphocytic leukemia[J]. Pharmacogenet Genomics,2006, 16(11): 783-788.
[215] 汪望月,夏冰,李春,等.核因子 κ b 抑制因子 α基因多态性与胃癌的相关性研究[J].中华胃肠外科杂志, 2007, 10(6): 585-586.
[216] Domagala-Kulawik J, Droszcz P, Kraszewska I, et al. Expression of Fas antigen in the cells from bronchoalveolar lavage fluid (BALF)[J]. Folia Histochem Cytobiol, 2000,38(4): 185-188.
[217] Kuwano K, Hagimoto N, Kawasaki M, et al. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis[J]. J Clin Invest, 1999, 104(1): 13-19.
[218] Borges V M,Falcao H,Leite-Junior J H,et al.Fas ligand triggers pulmonary silicosis[J].J Exp Med,2001,194(2): 155-164.
[219] Shen H M,Zhang Z,Zhang Q F,et al.Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages[J].Am J Physiol Lung Cell Mol Physiol,2001,280(1): L10-17.
[220] Borges V M,Lopes M F,Falcao H,et al.Apoptosis underlies immunopathogenic mechanisms in acute silicosis[J].Am J Respir Cell Mol Biol,2002,27(1): 78-84.
[221] Otsuki T,Miura Y,Nishimura Y,et al.Alterations of Fas and Fas-related molecules in patients with silicosis[J].Exp Biol Med (Maywood),2006,231(5): 522-533.
[222] 袁宝军，刘志忠，丁秀荣，等．煤工尘肺患者血清中可溶性Fas和FasL水平及临床意义[J]．中华劳动卫生职业病杂志，2006，24(2)：96-98．
[223] Bel Hadj Jrad B,Mahfouth W,Bouaouina N,et al.A polymorphism in FAS gene promoter associated with increased risk of nasopharyngeal carcinoma and correlated with anti-nuclear autoantibodies induction [J].Cancer Lett,2006,233 (1): 21-27.
[224] Sun T,Miao X,Zhang X,et al.Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma[J].J Natl Cancer Inst,2004,96(13): 1030-1036.
[225] Wu J,Metz C,Xu X,et al.A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients[J].J Immunol,2003,170(1): 132-138.
[226] Li C,Wu W,Liu J,et al.Functional polymorphisms in the promoter regions of the FAS and FAS ligand genes and risk of bladder cancer in south China: a case-control analysis[J].Pharmacogenet Genomics,2006,16(4): 245-251.
[227] Takahashi T,Tanaka M,Inazawa J,et al.Human Fas ligand: gene structure,chromosomal location and species specificity[J].Int Immunol,1994,6(10): 1567-1574.
[228] Qiu L X,Shi J,Yuan H,et al.FAS -1,377 G/A polymorphism is associated with cancer susceptibility: evidence from 10,564 cases and 12,075 controls[J].Hum Genet,2009.
[229] Chen J Y,Wang C M,Ma C C,et al.The -844C/T polymorphism in the Fas ligand promoter associates with Taiwanese SLE[J].Genes Immun,2005,6(2): 123-128.
[230] Farre L,Bittencourt A L,Silva-Santos G,et al.Fas 670 promoter polymorphism is associated to susceptibility,clinical presentation,and survival in adult T cell leukemia[J].J Leukoc Biol,2008,83(1): 220-222.
[231] Kanemitsu S,Ihara K,Saifddin A,et al.A functional polymorphism in fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus[J].J Rheumatol,2002,29(6): 1183-1188.
[232] Kordi Tamandani D M,Sobti R C,Shekari M.Association of Fas-670 gene polymorphism with risk of cervical cancer in North Indian population[J].Clin Exp Obstet Gynecol,2008,35(3): 183-186.
[233] Kang S,Dong S M,Seo S S,et al.FAS -1377 G/A polymorphism and the risk of lymph node metastasis in cervical cancer[J].Cancer Genet Cytogenet,2008,180(1): 1-5.
[234] Sun T,Zhou Y,Li H,et al.FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer[J].J Exp Med,2005,202(7): 967-974.
[235] Dybikowska A,Sliwinski W,Emerich J,et al.Evaluation of Fas gene promoter polymorphism in cervical cancer patients[J].Int J Mol Med,2004,14(3): 475-478.
[236] Engelmark M T,Renkema K Y,Gyllensten U B.No evidence of the involvement of the Fas -670 promoter polymorphism in cervical cancer in situ[J].Int J Cancer,2004,112(6): 1084-1085.
[237] Erdogan M,Karadeniz M,Berdeli A,et al.Fas/Fas ligand gene polymorphism in patients with papillary thyroid cancer in the Turkish population[J].J Endocrinol Invest,2007,30(5): 411-416.
[238] Gormus U,Ergen A,Yaylim-Eraltan I,et al.Fas-1377 A/G polymorphism in lung cancer[J].In Vivo,2007,21(4): 663-666.
[239] Huang Q R,Manolios N.Investigation of the -1377 polymorphism on the Apo-1/Fas promoter in systemic lupus erythematosus patients using allele-specific amplification[J].Pathology,2000,32(2): 126-130.
[1] 金泰廙，孙贵范，主编．职业卫生与职业医学[M]．北京：人民卫生出版社，2003，248-272．
[2] Kim KA,Cho YY,Cho JS,et al.Tumor necrosis factor-alpha gene promoter polymorphism in coal workers' pneumoconiosis [J].Mol Cell Biochem,2002,234-235(1-2):205-209.
[3] Corbett EL,Mozzato CN,Butterworth AE,et al.Polymorphisms in the tumor necrosis factor-α gene promoter may predispose to severe silicosis in black South African miners [J].Am J Respir Crit Care Med,2002,165(5): 690-693.
[4] 李霖，余晨，齐放，等．肿瘤坏死冈子-α及其Ⅱ型受体基因多态性与煤工尘肺[J]．中华劳动卫生职业病杂志，2004，22(4)：241-244．
[5] 李霖，余晨，齐放，等．肿瘤坏死因子-α及其Ⅱ型受体基因多态性与矽肺[J]．中华劳动卫生职业病杂志，2004，22(5)：323-326．
[6] 王德军，杨跃林，夏庆杰，等．肿瘤坏死因子-α基因多态性与矽肺遗传易感性的研究[J]．四川大学学报(医学版)，2005，36(5)：679-682．
[7] Wang XT,Ohtsuka Y,Kimura K.Antithetical effect of tumor necrosis factor-alpha gene polymorphism on coal workers' pneumoconiosis (CWP) [J].Am J Ind Med,2005,48(1):24-29.
[8] Meenagh A,Williams F,Ross OA,et al.Frequency of cytokine polymorphisms in populations from western Europe,Africa,Asia,the Middle East and South America [J].Hum Immunol,2002,63(11):1055-1061.
[9] 李娟．转化生长因子-β及基因多态性与纤维化的关系[J]．中华劳动卫生职业病杂志，2004，22(5)：382-385．
[10] Grainger D J,Heathcote K,Chiano M,et al.Genetic control of the circulating concentration of transforming growth factor type β1 [J].Hum Mol Genet,1999,8(1):93-97.
[11] Yamada Y,Miyauchi A,Goto J,et al.Association of a polymorphism of the transforming growth factor-beta 1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women [J].J Bone Miner Res,1998,13(10):1569-1576.
[12] Awad MR,El-Gamel A,Hasleton P,et al.Genotypic variation in the transforming growth factor-beta 1 gene: association with transforming growth factor-betal production,fibrotic lung disease,and graft fibrosis after lung transplantation [J].Transplantation,1998,66(8): 1014-1020.
[13] El-Gamel A,Awad MR,Hasleton PS,et al.Transforming growth factor-beta (TGF-beta 1) genotype and lung allograft fibrosis [J].J Heart Lung Transplant,1999,18(6):517-523.
[14] Arkwright PD,Laurie S,Super M,etal.TGF-β1 genotype and accelerated decline in lung function of patients with cystic fibrosis [J].Thorax,2000,55(6):459-462.
[15] Xaubet A,Main-Arguedas A,Lario S,et al.Transforming growth factor-beta 1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis [J].Am J Respir Crit Care Med,2003,168(4):431-435.
[16] 姚武，王治明，王绵珍等．煤工尘肺患者血清转化生长因子β1水平与其基因多态性的关系研究[J]．四川大学学报(医学版)，2005，36(6)：827-829．
[17] Yucesoy B,Vallyathan V,Landsittel DP,et al.Association of tumor necrosis factor and interleukin-1 gene polymorphisms with silicosis [J].Toxicol Appl Pharmacol,2001,172(1):75-82.
[18] Yucesoy B,Vallyathan V,Landsittel DP,et al.Polymorphislns of the IL-1 gene complex in coal miners with silicosis [J].Am J Ind Med,2001,39(3):286-291.
[19] 王明臣，刘红春，王俊萍等．煤工尘肺患者血清白细胞介素6及其可溶性受体含量的变化[J]．中国职业医学，2004，31(1)：25-26．
[20] Zhai R,Liu G,Ge X,et al.Serum levels of tumor necrosis factor-alpha (TNF-alpha),interleukin 6 (IL-6),and their soluble receptors in coal workers' pneumoconiosis [J].Respir Med,2002,96(10):829-834.
[21] Zhai R,Liu G,Yang C,et al.The G to C polyanorphism at -174 of the interleukin-6 gene is rare in a Southern Chinese population [J].Pharmacogenetics,2001,11(8): 699-701.
[22] Rihs HP,Lipps P,May-Taube K,et al.Immunogenetic studies on HLA-DR in German coal miners with and without coal worker's pneumoconiosis [J].Lung,1994,172(6):347-354.
[23] 李建强，宋满景，彭则．我国山西汉族煤工尘肺患者HLA-DRB1等位基因的调查[J]．中华劳动卫生职业病杂志，1999，17(2)：105-106．
[24] 袁宝军，张志欣，幸宏芬等．矽肺与人类白细胞抗原-DRB1~*和-DQB1~*基因相关性的研究[J]．中华劳动卫生职业病杂志，2002，20(2)：93-96．
[25] Zhai R.Liu G.Ge X,et al.Genetic polymorphisms of MnSOD,GSTM1,GSTT1,and OGG1 in coal workers' pneumoconiosis [J].J Occup Environ Med,2002,44(4):372-377.
[26] Yucesoy B,Johnson VJ,Kashon ML.Lack of association between antioxidant gene polymorphisms and progressive massive fibrosis in coal miners[J].Thorax,2005,60(6):492-495.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |