title: Genetic polymorphisms in alveolar macrophage response-related genes, and risk of silicosis and pulmonary tuberculosis in Chinese iron miners.
abstract: Alveolar macrophages (AMs) play a prominent role in influencing the development of lung inflammation and injury. The aim of this study is to investigate the roles of AMs response-related genes TNF-alpha, iNOS, and NRAMP1 (SLC11A1) in susceptibility to silicosis and pulmonary tuberculosis (PTB), and to analyze the interaction of dust exposure and genetic susceptibility to silicosis, interactions of TNF-alpha-308 and Natural Resistance-associated Macrophage Protein 1 (NRAMP1) INT4, D543N polymorphisms to PTB. Several epidemiological designs were used: retrospective investigations on dust exposure, case-control studies of 184 silicosis cases and 111 miners occupationally exposed to silica dust, and 1:2 matched case-control studies of 61 PTB cases and 122 PTB-free miners. The miners and controls were recruited from an iron mining operation in Anhui province, China. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was applied to detect single nucleotide polymorphisms. Despite the recruitment of high dust exposure among the controls, silicosis patients still had significantly higher dust exposure than controls (242.6 +/- 98.8 vs. 217.6 +/- 100.7 mg a/m(3)). The mutation of iNOS Ser608Leu is associated with protection against silicosis and against severity of silicosis in the miners. There is a 0.47-fold (95% CI: 0.28-0.79) decrease in risk of silicosis for individuals with C/T, T/T genotype compared with the wild-type homozygous (C/C) individuals after adjustment for occupational exposure, smoking, and drinking. The protection effect of the iNOS polymorphism was particularly detected in the > or = 150 mg a/m(3) exposure group (OR: 0.44, 95% CI: 0.22-0.91). However, no interaction of dust exposure with the iNOS polymorphism was observed. Furthermore, the variant NRAMP1 INT4 genotype is significantly associated with PTB in miners. No association of other polymorphisms (NRAMP1 D543N, TNF-alpha-308) and susceptibility to silicosis or PTB in Chinese miners was found. Our data showed a 3.26-fold (95% CI: 1.47-7.23) increased risk of PTB for miners carrying both the NRAMP1 D543N G/G and NRAMP1 INT4 G/C+C/C genotypes. Additionally, in miners with TNF-alpha-308 G/G genotype, the risk of PTB increased 2.38-fold if they carry the NRAMP1 INT4 G/C+C/C genotype (95% CI: 1.14-4.98). In conclusion, the C>T mutation of iNOS Ser608Leu may be an important protective factor to miners. On the other hand, the variant NRAMP1 INT4 may play a role in the development of PTB in Chinese miners. Therefore, the novel information can be used as guideline for further mechanistic investigations and for strengthening specific protection protocols for workers.
authors.affiliation: Department of Occupational Health and Toxicology, School of Public Health, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
authors.forename: Yabin
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Prevention and Health Care, Magang Hospital, Ma'anshan Iron and Steel Co. Ltd., Ma'anshan, Anhui 243003, China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Prevention and Health Care, Magang Hospital, Ma'anshan Iron and Steel Co. Ltd., Ma'anshan, Anhui 243003, China.
authors.forename: Duozhi
authors.initials: D
authors.lastname: Cao
authors.affiliation: Department of Occupational Health and Toxicology, School of Public Health, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Occupational Health and Toxicology, School of Public Health, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Occupational Health and Toxicology, School of Public Health, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Occupational Health and Toxicology, School of Public Health, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
authors.forename: Zhongbin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health and Toxicology, School of Public Health, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China. Electronic address: zlxia@shmu.edu.cn.
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000368:Aged; D000395:Air Pollutants, Occupational / Q000032:analysis / Q000633:toxicity*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D002681:China / Q000453:epidemiology; D004391:Dust / Q000032:analysis; D004784:Environmental Monitoring; D062665:Epidemiological Monitoring; D020022:Genetic Predisposition to Disease; D006801:Humans; D007501:Iron; D016676:Macrophages, Alveolar; D008297:Male; D008875:Middle Aged; D008906:Mining; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D016273:Occupational Exposure / Q000009:adverse effects / Q000032:analysis; D020641:Polymorphism, Single Nucleotide; D012822:Silicon Dioxide / Q000032:analysis / Q000633:toxicity*; D012829:Silicosis / Q000453:epidemiology / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D000395:Air Pollutants, Occupational; D027682:Cation Transport Proteins; D004391:Dust; D007501:Iron; D052247:Nitric Oxide Synthase Type II; D012822:Silicon Dioxide; D014409:Tumor Necrosis Factor-alpha; D000099173:Natural Resistance-associated Macrophage Protein 1; C496319:NOS2 protein, human