Genetic susceptibility in pneumoconiosis in China: a systematic review.

OBJECTIVE: Pneumoconiosis, encompassing coal workers' pneumoconiosis (CWP), silicosis and asbestosis, is one of the most common occupational diseases in China. Previous studies revealed significant associations between genetic variations and pneumoconiosis risk among individuals in different countries. With the known variability of genetic makeup between ethnicities, susceptibility to pneumoconiosis due to genetic differences is likely to be ethnicity-specific. The present review aimed at providing a comprehensive overview on the association between genetic polymorphisms and susceptibility of pneumoconiosis, specifically among people in China. METHODS: The literature search was performed in seven English and Chinese databases using keywords related to the review aim. An appraisal of the methodological quality of the included studies was conducted using the assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. RESULTS: Forty-five studies were included in this review. Genotypes of specific genes which are associated with the risk of CWP, silicosis and asbestosis were reported. Our findings showed that genes encoding inflammatory cytokines have been examined extensively, and they demonstrated an association between these genes and pneumoconiosis risk. Gene-environment interactions in pneumoconiosis susceptibility were also reported by a number of studies. CONCLUSIONS: This review summarised the evidence demonstrating the association between genetic polymorphisms and pneumoconiosis susceptibility among people in China, and that various genotypes could modify their risk to develop pneumoconiosis. The findings prompt that identification of individuals at high pneumoconiosis risk through genetic screening and strategies limiting their exposure to dust could be a potential strategy for the control of this occupational disease in China.

Exosomal miRNAs contribute to coal dust particle-induced pulmonary fibrosis in rats.

Coal workers' pneumoconiosis (CWP) is a fatal occupational disease caused by inhalation of coal dust particles, which leads to progressive pulmonary fibrosis. Recently, as new signal carriers for intercellular communication, exosomal miRNAs have been validated in the pathogenesis of multiple diseases. However, the research on exosomal miRNAs in CWP is still in the preliminary stage. Here, using miRNA sequencing, exosomal miRNA profiles in bronchoalveolar lavage fluid (BALF) from rats with pulmonary fibrosis induced by coal dust particles were analyzed, and the underlying biological function of putative target genes was explored by GO term analysis and KEGG pathway enrichment analysis. According to the results, intratracheal instillation of coal dust particles can alter the exosomal miRNAs expression in the BALF of rats. Further bioinformatics analysis provided some clues to reveal their function in pathological process of pneumoconiosis. More importantly, we identified 4 differentially expressed exosomal miRNAs (miRNA-21-5p, miRNA-29a-3p, miRNA-26a-5p, and miRNA-34a-5p) by qRT­PCR and further verified the temporal changes in the expression of these exosomal miRNAs in animal models from 2 weeks to 16 weeks postexposure. In addition, we conducted a preliminary study on Smad7 as a potential target of miRNA-21-5p and found that exosomal miRNA 21-5p/Smad7 may contribute to the pulmonary fibrosis induced by coal dust particles. Our study confirmed the contribution of exosomal miRNAs to coal dust particle-induced pulmonary fibrosis and provided new insights into the pathogenesis of CWP.

Transcriptome-wide association study identifies PSMB9 as a susceptibility gene for coal workers' pneumoconiosis.

Coal workers' pneumoconiosis (CWP) is a type of typical occupational lung disease caused by prolonged inhalation of coal mine dust. The individuals' different genetic background may underlie their different susceptibility to develop pneumoconiosis, even under the same exposure level. This study aimed to identify susceptibility genes associated with CWP. Based on our previous genome-wide association study (GWAS, 202 CWP cases vs. 198 controls) and gene expression data obtained by analyzing human lungs and whole blood from the Genotype-Tissue Expression (GTEx) Portal, a transcriptome-wide association study (TWAS) was applied to identify CWP risk-related genes. Luciferase report gene assay, qRT-PCR, Western blot, immunofluorescence assay, and TUNEL assay were conducted to explore the potential role of the candidate gene in CWP. Proteasome 20S subunit beta 9 (PSMB9) was identified as a strong risk-related gene of CWP in both lungs and whole blood (Lungs: PTWAS  = 4.22 × 10-4 ; Whole blood: PTWAS  = 2.11 × 10-4 ). Single nucleotide polymorphisms (SNPs) rs2071480 and rs1351383, which locate in the promoter region and the first intron of the PSMB9 gene, were in high linkage disequilibrium (LD, r2  = 0.98) with the best GWAS SNP rs4713600 (G>T, OR = 0.55, 95% CI: 0.42-0.74, P = 6.86 × 10-5 ). Both rs2071480 and rs1351383 significantly enhanced the transcriptional activity of PSMB9. Functional experiments revealed that silica exposure remarkably reduced the PSMB9 expression and caused cell apoptosis, while overexpression of PSMB9 markedly abolished silica-induced cell apoptosis. We here identified PSMB9 as a novel susceptibility gene for CWP and provided important insights into the further exploration of the CWP pathogenesis.

[Expression and functional SNP loci screen of ATM from coal worker's pneumoconiosis].

Objective: To detect of gene expression and genotype of the ataxia telangiectasia mutated (ATM) from coal workers' pneumoconiosis (CWP) , It is explored whether CWP is related to ATM gene. Methods: In October 2020, the relevant information of 264 subjects who received physical examination or medical treatment in the Department of occupational diseases of Guiyang public health treatment center from January 2019 to September 2020 was collected. Through the occupational health examination, 67 healthy people with no history of exposure to occupational hazards were selected as the healthy control group; The coal miners with more than 10 years of coal dust exposure history and small shadow in the lung but not up to the diagnostic criteria were the dust exposure control group, a total of 66 people; The patients with the same history of coal dust exposure and confirmed stage I were coal worker's pneumoconiosis stage I group, a total of 131 people. The expression of ATM was detected by QRT PCR. ATM rs189037 and rs1801516 were genotyped by massarray. Results: There was significant difference in the expression of ATM among the groups (P<0.05) ; Compared with the healthy control group, the expression of ATM in the dust exposed control group was significantly increased (P<0.05) . With the occurrence and development of CWP, the GG of rs189037 wild type decreased, the GA of mutant heterozygote and AA of homozygote increased, but the difference was not statistically significant (P>0.05) ; Rs1801516 wild type GG and mutant heterozygote GA had no significant changes (P>0.05) . There were significant differences in age, neutrophils and basophils among rs189037 groups (all P<0.05) . There were no significant differences in blood pressure, eosinophils, lymphocytes, monocytes, smoking and drinking history among rs189037 groups (all P>0.05) . Compared with wild-type GG, the or of mutant heterozygotes and homozygotes increased, but the differences were not statistically significant (P>0.05) . Conclusion: ATM gene may be one of the early activation genes of CWP and rs189037 may be the functional loci which affects gene expression. ATM gene is related to inflammatory response, Neutrophils and basophils have an impact on the development of CWP.

Expression and functional SNP loci screen of ATM from coal worker's pneumoconiosis / 中华劳动卫生职业病杂志

Objective: To detect of gene expression and genotype of the ataxia telangiectasia mutated (ATM) from coal workers' pneumoconiosis (CWP) , It is explored whether CWP is related to ATM gene. Methods: In October 2020, the relevant information of 264 subjects who received physical examination or medical treatment in the Department of occupational diseases of Guiyang public health treatment center from January 2019 to September 2020 was collected. Through the occupational health examination, 67 healthy people with no history of exposure to occupational hazards were selected as the healthy control group; The coal miners with more than 10 years of coal dust exposure history and small shadow in the lung but not up to the diagnostic criteria were the dust exposure control group, a total of 66 people; The patients with the same history of coal dust exposure and confirmed stage I were coal worker's pneumoconiosis stage I group, a total of 131 people. The expression of ATM was detected by QRT PCR. ATM rs189037 and rs1801516 were genotyped by massarray. Results: There was significant difference in the expression of ATM among the groups (P<0.05) ; Compared with the healthy control group, the expression of ATM in the dust exposed control group was significantly increased (P<0.05) . With the occurrence and development of CWP, the GG of rs189037 wild type decreased, the GA of mutant heterozygote and AA of homozygote increased, but the difference was not statistically significant (P>0.05) ; Rs1801516 wild type GG and mutant heterozygote GA had no significant changes (P>0.05) . There were significant differences in age, neutrophils and basophils among rs189037 groups (all P<0.05) . There were no significant differences in blood pressure, eosinophils, lymphocytes, monocytes, smoking and drinking history among rs189037 groups (all P>0.05) . Compared with wild-type GG, the or of mutant heterozygotes and homozygotes increased, but the differences were not statistically significant (P>0.05) . Conclusion: ATM gene may be one of the early activation genes of CWP and rs189037 may be the functional loci which affects gene expression. ATM gene is related to inflammatory response, Neutrophils and basophils have an impact on the development of CWP.

Heterozygous Ins/Del genotype of the CASP8 rs3834129 polymorphism significantly decreases the risk of coal workers' pneumoconiosis in a Chinese Han population: a case-control study.

OBJECTIVE: Coal workers' pneumoconiosis (CWP) is a chronic inflammatory and fibrotic pulmonary disease that involves a complex interaction of multiple environmental and genetic factors. Polymorphism, as a genetic factor, may affect the onset of the disease in susceptible populations. The present study investigated the association between the polymorphisms of six genes and CWP risk in a Chinese Han population. PATIENTS AND METHODS: Six polymorphisms (CASP8 rs3834129, IL1A rs1800587, IL6 rs1800796, IL4 rs2070874, TNFA rs361525, and NLRP3 rs1539019) were examined in 222 CWP subjects and 247 dust-exposed control subjects. RESULTS: The CASP8 rs3834129 Ins/Del genotype significantly decreased CWP risk (p=0.040; adjusted odds ratio [OR] = 0.586; 95% confidence interval [CI] 0.367-0.935) compared with the Ins/Ins genotype. Stratification analyses revealed a significant interaction between the heterozygous Ins/Del genotype and age. Compared with the Ins/Ins + Del/Del genotype, this was particularly evident among subjects aged 41-60 (p<0.001; adjusted OR = 0.054; 95% CI 0.007-0.420) and those with an exposure time of 20-29 years (p=0.014; adjusted OR = 0.392; 95% CI 0.183-0.842). This decreased risk was also found in the group with former smokers (p=0.012; adjusted OR = 0.448; 95% CI 0.238-0.844). Findings revealed that the heterozygous Ins/Del genotype of CASP8 rs3834129 was related to a significantly decreased risk of stage I CWP (p=0.045; adjusted OR = 0.592; 95% CI 0.353-0.992), but not stage II or III CWP. CONCLUSIONS: Our study indicated that the heterozygous Ins/Del genotype of CASP8 rs3834129 significantly decreased CWP risk in a Chinese Han population.

Respiratory traits and coal workers' pneumoconiosis: Mendelian randomisation and association analysis.

OBJECTIVES: Susceptibility loci of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were also significantly associated with the predisposition of coal worker's pneumoconiosis (CWP) in recent studies. However, only a few genes and loci were targeted in previous studies. METHODS: To systematically evaluate the genetic associations between CWP and other respiratory traits, we reviewed the reported genome-wide association study loci of five respiratory traits and then conducted a Mendelian randomisation study and a two-stage genetic association study. RESULTS: Interestingly, we found that for each SD unit, higher lung function was associated with a 66% lower risk of CWP (OR=0.34, 95% CI: 0.15 to 0.77, p=0.010) using conventional Mendelian randomisation analysis (inverse variance weighted method). Moreover, we found susceptibility loci of interstitial lung disease (rs2609255, OR=1.29, p=1.61×10-4) and lung function (rs4651005, OR=1.39, p=1.62×10-3; rs985256, OR=0.73, p=8.24×10-4 and rs6539952, OR=1.28, p=4.32×10-4) were also significantly associated with the risk of CWP. Functional annotation showed these variants were significantly associated with the expression of FAM13A (rs2609255, p=7.4 ×10-4), ANGPTL1 (rs4651005, p=5.4 ×10-7), SPATS2L (rs985256, p=1.1 ×10-5) and RP11-463O9.9 (rs6539952, p=7.1 ×10-6) in normal lung tissues, which were related to autophagy pathway simultaneously according to enrichment analysis. CONCLUSIONS: These results provided a deeper understanding of the genetic predisposition basis of CWP.

Associations of HMGB1 gene polymorphisms with risk of coal workers' pneumoconiosis susceptibility in Chinese Han population.

Background: High-mobility group box 1 (HMGB1) protein plays an important pathogenic role in various diseases such as pulmonary fibrosis. However, the relationship between variation of HMGB1 gene and susceptibility to coal worker's pneumoconiosis (CWP) remains unclear. The objective of the study was to determine the association between HMGB1 polymorphisms and CWP in Chinese Han population.Methods: The genotypes of HMGB1 gene rs1045411, rs2249825, rs1412125 and rs1360485 in 340 CWP patients and 312 healthy controls were determined and serum HMGB1 levels were detected.Results: Our finding showed that the HMGB1 rs1360485 G allele increased the risk of CWP in comparison with A allele (P = 0.005). HMGB1 rs1360485 GG genotype as well as AG+GG genotype increased the risk of CWP in comparison with AA genotype (P = 0.010, P = 0.025, respectively). Four haplotypes were identified and we found that the GCTA haplotype was associated with resistance to CWP (P = 0.005), while GCTG haplotype was associated with risk to CWP (P<0.001). Meanwhile, multifactor dimensionality reduction (MDR) analysis showed that the interaction between rs1360485 and exposure had the strongest, followed by rs2249825 and rs1412125. This study also found that the serum HMGB1 levels of the case group were significantly higher than that of the control group, and the serum HMGB1 levels of homozygous subjects with rs1360485 mutant were higher than that of the heterozygous wild type, respectively (P<0.001). Meanwhile, the levels of HMGB1 with GCTA haplotype was lower than with GCTG haplotype (P<0.001)Conclusion: Our findings indicated that HMGB1 gene rs1360485 polymorphism was associated with the susceptibility to CWP in Chinese Han population.

NAF1 rs4691896 Is Significantly Associated with Coal Workers' Pneumoconiosis in a Chinese Han Population: A Case-Control Study.

BACKGROUND Previous studies have demonstrated the important role of genetic predisposition in coal workers' pneumoconiosis (CWP) in addition to environmental factors. The pathogenesis of pulmonary fibrosis disease is related to telomere activity. We performed this study to assess the association between genetic variants of telomere-related genes and the risk of CWP. MATERIAL AND METHODS We enrolled 652 CWP Chinese Han patients and 648 dust-exposed controls in this case-control design study, genotyping 8 single-nucleotide polymorphisms (SNPs) including TERT (rs2736100), TERC (rs10936599 and rs12696304), and NAF1 (rs7675998, rs3822304, rs12331717, rs936562 and rs4691896) using the Sequenom MassARRAY system. RESULTS We identified a significant allele association between NAF1 rs4691896 and CWP by comparing patients with controls (22.0% vs. 13.0%, odds ratio [OR]: 1.89, 95% confidence interval [CI]: 1.54-2.33, Pc=1.14×10⁻8). The genotype frequency of rs4691896 differed significantly between the patients and controls (Pc=1.49×10⁻8). In addition, rs4691896 was correlated with CWP in an additive genetic model (OR: 1.96, 95% CI: 1.58-2.44, Pc=8.96×10⁻9) and a dominant model (OR: 2.15, 95% CI: 1.70-2.73, Pc=2.39×10⁻9). CONCLUSIONS Our study for the first time demonstrates an association between a telomere-related gene (NAF1) and CWP in a Chinese Han population, and provides valuable insight to further understand the possible pathogenetic mechanism of fibrosis in CWP.

Colletotrichum Species Associated with Japanese Plum (Prunus salicina) Anthracnose in South Korea.

A total of 24 Colletotrichum isolates were isolated from diseased Japanese plum (Prunus salicina) fruits showing chlorotic regions with whitish-brown sunken necrotic lesions and phylogenetic relationships among the collected Colletotrichum isolates were determined. A subset of 11 isolates was chosen for further taxonomic study based on morphology and molecular characteristics identified using the internal transcribed spacer (ITS) and beta-tubulin (TUB2) genes. Isolates in the C. acutatum complex were analyzed using partial sequencing of five gene regions (ITS, GAPDH, ACT, TUB2, and CHS), and C. gloeosporioides sensu lato (s.l.) isolates were analyzed using seven gene regions (ITS, TUB2, GAPDH, ACT, CAL, CHS-1, and ApMat). Morphological assessments in combination with phylogenetic analysis delineated four species of Colletotrichum including C. gloeosporioides sensu stricto (s.s.), C. nymphaeae, C. foriniae, and C. siamense; these data identify Colletotrichum fioriniae and C. siamense two new species associated with plum anthracnose in South Korea. Finally, the pathogenicity of these four species in the development of plum anthracnose in South Korea was confirmed by inoculations of plum fruit.

Dust induces lung fibrosis through dysregulated DNA methylation.

Pneumoconiosis is a serious occupational disease that often occurs to coal workers with no early diagnosis and effective treatment at present. Diffuse pulmonary fibrosis is the major pathological change of pneumoconiosis, and its mechanism is still unclear. Epigenetics is involved in the development of many diseases, and it is closely associated with fibrosis. In this study, we investigated whether DNA methylation contributes to the pathogenesis of pulmonary fibrosis in pneumoconiosis. By exposure to coal dust or silica dust, we established the models of coal worker's pneumoconiosis (CWP), which showed an increased expression of COL-I, COL-III. We further found that DNMT1, DNMT3a, DNMT3b, MBD2, MeCP2 protein expression changed. Pretreatment with DNMT inhibitor 5-aza-dC reduced expression of COL-I, COL-III, and reduced pulmonary fibrosis. In summary, our results showed that DNA methylation contributes to dust-induced pulmonary fibrosis and that it may serve as a theoretical basis for testing DNA methyltransferase inhibitors in the treatment of CWP.

TNF-α-TNFR signal pathway inhibits autophagy and promotes apoptosis of alveolar macrophages in coal worker's pneumoconiosis.

OBJECTIVE: Exposure to coal dust causes the development of coal worker's pneumoconiosis (CWP), which is associated with accumulating macrophages in the lower respiratory tract. This study was performed to investigate the effect of tumor necrosis factor-α (TNF-α)-tumor necrosis factor receptor (TNFR) signal pathway on autophagy and apoptosis of alveolar macrophages (AMs) in CWP. METHODS: AMs from controls exposed to coal dust and CWP patients were collected, in which expressions of TNF-α and TNFR1 were determined. Autophagy was observed by transmission electron microscopy, and apoptosis by light microscope and using terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. AMs in CWP patients were treated with TNF-α or anti-TNF-α antibody. Besides, expressions of autophagy marker proteins, apoptosis-related factors, FAS, caspase-8, and receptor-interacting serine-threonine-protein kinase 3 (RIPK3) were determined by western Blot. Activities of caspase-3 and caspase-8 were determined by a fluorescence kit. Flow cytometry was applied to measure the expression of TNFR1 on the surface of the AM. RESULTS: TNF-α expression and TNFR1 expression on the surface of AM, as well as autophagy and apoptotic index were significantly increased in AMs of CWP patients. In response to the treatment of TNF-α, TNF-α expression and TNFR1 expression on the surface of AM as well as LC3I expression were increased, autophagy was decreased, and LC3, LC3II, Beclin1 and B-cell lymphoma 2 expressions decreased, whereas FAS expression and activity and expression of caspase-3 and caspase-8 increased, and apoptotic index increased. Moreover, the situations were reversed with the treatment of anti-TNF-α antibody. CONCLUSION: TNF-α-TNFR signal pathway was involved in the occurrence and development of CWP by activating FAS-caspase-8 and thus inhibiting autophagy while promoting apoptosis of AM.

Association between tumor necrosis factor-α -308 Gauss/A polymorphism and risk of silicosis and coal workers pneumoconiosis in Chinese population.

BACKGROUND: Many studies have attempted to clarify the association between TNF-a -308G/A polymorphism and pneumoconiosis, but there has been no definite consensus to date. To further assess the effects of TNF-a -308G/A polymorphism on the risk of pneumoconiosis, a meta-analysis was performed in Chinese population. METHODS: We searched the related literature in PubMed and Chinese databases through June 2018. The strength of the associations was assessed used pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Nine case-control studies including 730 silicosis cases, 457 coal workers pneumoconiosis cases and 2429 controls were identified according to the inclusion criteria. In the total analyses, a significantly elevated risk was found in allelic model (OR = 1.41, 95% CI = 1.16-1.71). In the subgroup analyses by geographic area and type of pneumoconiosis, significant results were found both in North China (A versus G, OR = 1.33, CI = 1.05-1.69) and South China (A versus G, OR = 1.56, CI = 1.14-2.15); significant results were also found in silicosis (A versus G, OR = 1.40, CI = 1.11-1.78) and coal worker pneumoconiosis (A versus G, OR = 1.42, CI = 1.03-1.96). CONCLUSION: This meta-analysis suggested that TNF-a gene -308 G/A polymorphism is associated with increased silicosis and coal workers pneumoconiosis risk in the Chinese population, and further studies in other ethnic groups are required for definite conclusions.

Association Analysis Identifies New Risk Loci for Coal Workers' Pneumoconiosis in Han Chinese Men.

Coal worker's pneumoconiosis (CWP) is a debilitating and progressive occupational lung disease resulted from long-term inhalation of airborne silica-containing coal mine dust. Both environmental factors and genetic variations contribute to CWP. Our previous genome-wide association study (GWAS) revealed a tiny fraction of variants with the top associations in Chinese Han population. To identify novel susceptibility loci of CWP, functional variants with suboptimal associations in the GWAS scan were further studied here. Imputation was firstly performed to access the associations between ungenotyped variants and CWP risk, and suboptimal associations with p < 1.0 × 10-3 were annotated with genotype-tissue expression (GTEx) and dbNSFP. Further, expression quantitative trait loci (eQTL) and nonsynonymous variants were validated within an independent cohort with 703 CWP cases and 705 exposed controls. Comprehensively functional annotations were performed for identified single nucleotide polymorphism (SNPs) based on multiple bioinformatics databases and websites. We found 4 CWP risk-associated eQTL SNPs, including rs10797062 at 1q23.2 (p = 6.91 × 10-4, OR = 1.28), rs1667614 at 2q13.1 (p = 1.48 × 10-4, OR = 0.53), rs2540438 at 2q33.1 (p = 2.13 × 10-3, OR = 1.33), and rs2274554 at 13q31.1 (p = 9.01 × 10-5, OR = 1.35). Based on the results from GTEx, the identified variants were significantly associated with host genes in lung tissues: rs10797062-ATP1A4 (p = 8.60 × 10-11), rs1667614-FNBP1P1 (p = 1.00 × 10-20), rs2540438-ALS2CR12 (p = 1.90 × 10-7), and rs2274554-RBM26 (p = 5.00 × 10-6). Joint effect analysis showed the risk of CWP was significantly increased with the number of risk variant alleles in an allele-dosage manner (ptrend = 2.20 × 10-12). Enrichment pathway analysis suggested coexpressed genes of ATP1A4, FNBP1P1, and RBM26 were enriched in Ubiquitin mediated proteolysis pathway simultaneously. These results may provide a deeper understanding of the genetic predisposition of CWP.

Association of single nucleotide polymorphisms in the CYBA gene with coal workers' pneumoconiosis in the Han Chinese population.

Coal workers' pneumoconiosis (CWP) is caused by long-term exposure to inhaled coal dust; it is likely influenced by the interaction between environmental factors and multiple susceptibility genes, such as the CYBA (cytochrome b-245α polypeptide) gene that has recently been identified to be involved in the genetic susceptibility for several pulmonary diseases. The aim of this case-control study was to explore the association between CYBA gene polymorphisms and the development of CWP in coal miners belonging to the Han ethnic group in China. Single nucleotide polymorphisms (SNPs) rs7195830, rs13306296, rs4673, rs9932581, and rs16966671 of the CYBA gene were analyzed in CWP patients (n = 652) and dust-exposed control subjects (n = 648) using the matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) on the Sequenom MassARRAY® platform (Sequenom, San Diego, CA, USA). Results from the present study showed a strong allele association between CWP patients and the CYBA SNP rs7195830 polymorphism (p < .001, OR = 1.550). Using the additive and the dominant model, the CYBA SNP rs7195830 polymorphism also showed significant associations with CWP patients (p < .001, OR = 1.621; p = .003, OR = 1.711, respectively). No statistically significant difference was demonstrated in either the allele or genotype frequencies of the other four examined SNPs (rs13306296, rs4673, rs9932581, and rs16966671) between the CWP group and dust-exposed control group (all p > .05). The present study is the first to have demonstrated an association between CYBA (rs7195830) polymorphism and the risk of developing CWP in subjects belong to the Han ethnic group in China and provides further clues for research into the pathogenesis of CWP.

Polymorphisms in autophagy related genes and the coal workers' pneumoconiosis in a Chinese population.

Autophagy is an evolutionary conserved intracellular degradation/recycling system that is essential for cellular homeostasis. Dysregulation of this process leads to a number of disorders, including pulmonary fibrosis. However, the genetic association between singe nucleotide polymorphisms of autophagy related genes (ATGs) and the risk of coal workers' pneumoconiosis has not been reported yet. Total of 7 SNPs in ATGs (ATG16, ATG12, ATG5, ATG10) were investigated for their roles in CWP by a case-control study which including 705 CWP patients and 703 control subjects. Genotyping were performed by the Sequenom Mass ARRAY system. Luciferase assays were taken to test the effects of rs26538 C>T on the activity of ATG12 in the promoter. Our data showed that ATG10 rs1864182 GT genotype was associated with a decreased risk of CWP compared with TT genotype (OR=0.42, 95% CI=0.33-0.54, P=0.001). Another 2 SNPs (rs26538, rs510432) were also with the marked decreases in the risk of CWP under recessive models (OR=0.58, 95% CI=0.40-0.83, P=0.002 for rs26538; OR=0.74, 95% CI=0.57-0.97, P=0.040 for rs510432). Luciferase assays in two different cell lines revealed that the rs26538 C>T substitution could reduce the expression of ATG12. Taken together, we identified three SNPs in ATGs, which implicated the development of CWP. Further studies are warranted to validate these findings.

The association of LAMB1 polymorphism and expression changes with the risk of coal workers' pneumoconiosis.

BACKGROUND: Pneumoconiosis is a serious occupational disease worldwide, which is characterized by irreversible and diffuse lung fibrotic lesions. Laminin beta 1(LAMB1) is widely expressed in tissues and it is crucial for both lung morphogenesis and physiological function. In this study, we explored the association between LAMB1 rs4320486 and risk of pneumoconiosis in a Chinese population, as well as its mechanisms. METHODS: In this case-control study, 600 CWP patients and 605 controls were genotyped for the LAMB1 rs4320486 polymorphism using TaqMan methods. Luciferase reporter assay was used to assess the LAMB1 transcriptional activities. The protein levels in cells and tissues were detected by western blot, and mRNA levels were determined by qRT-PCR. RESULTS: Logistic regression analysis revealed that individuals with LAMB1 rs4320486 CT/TT genotypes had a significantly decreased risk of CWP (adjusted OR = 0.78, 95%CI = 0.64-0.94), compared with individuals with CC genotypes. Luciferase assays showed that the LAMB1 rs4320486(C > T) substitution could decrease the expression of LAMB1. Compared with normal groups, mRNA levels of LAMB1 were up-regulated in lung tissues of patients with pulmonary fibrosis. Additionally, expressions of LAMB1 and α-SMA were enhanced progressively, along with the development of lung fibrosis, while E-cadherin decreased. CONCLUSIONS: In this study, the functional LAMB1 rs4320486 mutation was associated with a decreased risk of CWP in a Chinese population, probably owing to the reduced activity of LAMB1 transcription. LAMB1 expression was increased in the progress of lung fibrosis, which suggests that LAMB1 may affect the initiation and progression of pneumoconiosis, or serve as a potential biomarker of pneumoconiosis for diagnosis and genetic susceptibility.

Polymorphisms in Long Noncoding RNA H19 Contribute to the Protective Effects of Coal Workers' Pneumoconiosis in a Chinese Population.

The H19 is a kind of long noncoding RNA, which has been implicated in multiple biological functions. However, the associations between genetic variants in H19 and susceptibility of coal workers' pneumoconiosis (CWP) have been seldom reported. In the present study, three potential polymorphisms (rs2067051, rs217727, and rs2839702) in H19 were genotyped in a case-control study including 703 CWP cases and 705 controls. We found that individuals with the H19 rs2067051 CT/TT genotypes showed a decreased risk of CWP compared with those with the CC genotype (adjusted OR = 0.64, 95%CI = 0.49-0.83, p = 0.001). Further stratified analyses revealed that the associations between variant genotypes of rs2067051 and the risk of CWP were more prominent in subjects of non-smokers (adjusted OR = 0.55, 95%CI = 0.39-0.79, p = 0.001) and CWP patients with Stage I (adjusted OR = 0.63, 95%CI = 0.46-0.86, p = 0.004). Additionally, the protective effects of H19 rs2067051 were also evident in coal miners both with dust exposure years <25 years (adjusted OR = 0.63, 95%CI = 0.42-0.95, p = 0.026) and ≥25 years (adjusted OR = 0.57, 95%CI = 0.40-0.80, p = 0.001). Our results indicated that rs2067051 in the H19 gene is correlated with a deceased risk of CWP in a Chinese population, which may be a potential genetic marker for prevention and intervention of CWP. Further functional studies are warranted to validate our findings.

[HSP70 gene polymorphism on genetic susceptibility to the coal worker's penumoconiosis of han nationality in Xinjiang, China.]

Objective: To explore the influence of heat shock protein 70 (HSP70) gene genetic susceptibility of coal worker's pneumoconiosis among the han nationality in xinjiang. Methods: 156 coal worker's pneumoconiosis patients and 96 mine workers were randomly selected from the han coal worker's pneumoconiosis patients and attend the health check retirement mine workers from March to December, 2014 in Xinjiang Uygur Autonomous Region of Occupational Disease Hospital. Using TaqMan genotyping methods to detect HSP70 genotype distribution in the two groups. Results: The HSP70-1+190 loci GC genotype occurrence frequencies of coal worker's pneumoconiosis was significantly higher than the control group (χ2=6.75, P<0.05) , the risk of coal worker's pneumoconiosis armed with HSP70-1+190 GC genotype individual was 2.21 times of CC genotype individual (95%CI: 1.03~4.75) , and HSP70-2+1267 and HSP70-hom+2437 loci polymorphism were no significant difference between the two groups (HSP70-2+1267: χ2=3.30, P=0.19; HSP70-hom+2437: χ2=0.12, P=0.94) . Conclusion: HSP70-1+190 GC genotypes may be a susceptible genotype, the genotype individual may be more likely to suffer from coal worker's pneumoconiosis.

Differential gene expression associated with inflammation in peripheral blood cells of patients with pneumoconiosis.

OBJECTIVES: To study expression changes in inflammation-related genes in peripheral blood of patients with pneumoconiosis and to explore the possibility of these genes as pneumoconiosis biomarkers. METHODS: Peripheral blood samples of patients with pneumoconiosis patients and controls were collected, and total RNA of the blood cells were extracted and reverse transcribed to cDNA. Screenings of deferentially expressed genes associated with inflammation between patients with pneumoconiosis and controls were performed using real-time quantitative PCR array and the expressions of the three most upregulated genes were confirmed by real-time PCR. RESULTS: The expression of 11 genes was significantly altered in patients with pneumoconiosis compared with those of the control. Among these 11 genes, 8 genes were upregulated and 3 were downregulated. Preliminary results indicated that interleukin 6 (IL-6) mRNA expression in patients with pneumoconiosis was higher than that in controls (P=0.019). The level of IL6 mRNA expression in the patients was higher than that in non-smoking controls, but it was neither affected by type and stage of pneumoconiosis nor by time of contact with dust. CONCLUSIONS: IL6 was possibly involved in the development of pneumoconiosis.