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.

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.

[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.

Polymorphisms in inflammasome genes and risk of coal workers' pneumoconiosis in a Chinese population.

BACKGROUND: Coal workers' pneumoconiosis (CWP), resulting from the inhalation of silica-containing coal mine dust, is characterized by fibrosing nodular lesions that eventually develop into progressive pulmonary fibrosis. Recently, it has been hypothesized that inflammasomes could have a crucial role in the host response to silica and recent studies show that the inflammasome contributes to inflammation and pulmonary fibrosis. NLRP3, CARD8 are components of the NLRP3 inflammasome, which triggers caspase 1-mediated IL-1ß and IL-18 release. In the present study, we investigated whether common single nucleotide polymorphisms (SNPs) in inflammasome genes are associated with CWP. METHODS: We performed an association study analyzing 3 NLRP3, 1 CARD8, 1 IL-1ß, 2 IL-18 SNPs in a case-control study of 697 CWP and 694 controls. Genotyping was carried out by the TaqMan method. RESULTS: The NLRP3 rs1539019 TT genotype was associated with a significantly increased risk of CWP (adjusted odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.07-1.81), compared with the GG/GT genotype, in particular among smokers (adjusted OR = 1.67, 95%CI = 1.15-2.42). In addition, the polymorphism was significantly associated with risk of CWP patients with stage I. CONCLUSIONS: This is the first report showing an association between the NLRP3 rs1539019 polymorphism and CWP, and suggests that this polymorphism may confer increased risk for the development of the disease. Further studies are warranted to confirm our findings.

Associations of IL-4, IL-4R, and IL-13 gene polymorphisms in coal workers' pneumoconiosis in China: a case-control study.

BACKGROUND: The IL-4, IL-4 receptor (IL4R), and IL-13 genes are crucial immune factors and may influence the course of various diseases. In the present study, we investigated the association between the potential functional polymorphisms in IL-4, IL-4R, and IL-13 and coal workers' pneumoconiosis (CWP) risk in a Chinese population. METHODS: Six polymorphisms (C-590T in IL-4, Ile50Val, Ser478Pro, and Gln551Arg in IL-4R, C-1055T and Arg130Gln in IL-13) were genotyped and analyzed in a case-control study of 556 CWP and 541 control subjects. RESULTS: Our results revealed that the IL-4 CT/CC genotypes were associated with a significantly decreased risk of CWP (odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.58-0.95), compared with the TT genotype, particularly among subgroups of age <65 years (OR = 0.68, 95%CI = 0.46-0.99) and dust exposure years ≥26 years (OR = 0.69, 95%CI = 0.50-0.94). Moreover, the polymorphism was significantly associated with risk of CWP patients with stage I. In addition, a combined effect was observed in a dose-dependent manner with increasing numbers of risk variant alleles (P(trend) = 0.023), and individuals with 11-12 risk alleles had a 47% higher risk of CWP than those with 0-8 risk alleles (OR = 1.47, 95% CI = 1.05-2.05). CONCLUSIONS: Our results suggest that the IL-4 C-590T polymorphism is involved in the etiology of CWP and susceptibility to this disease. Larger studies are warranted to validate our findings.

Polymorphisms in heat-shock protein 70 genes are associated with coal workers' pneumoconiosis in southwestern China.

BACKGROUND: Heat-shock proteins (HSPs) protect cells and tissues against different types of damage. This study investigated the relationship between the genetic variation in constitutive and inducible HSP70 genes and the risk for coal workers' pneumoconiosis (CWP) among miners in southwestern China. PATIENTS AND METHODS: A job exposure matrix (JEM) was used to estimate the dust exposure level of individuals. A total of 225 CWP patients and 294 healthy individuals were assessed by genotyping for the single-nucleotide polymorphisms (SNPs) of the HSP70-1 (190 G/C), HSP70-2 (1267 A/G), and HSP70-hom (2437 T/C) genes. The association between these polymorphisms and the risk for CWP was assessed. RESULTS: Polymerase chain reaction-restriction fragment length polymorphism analysis revealed no statistically significant differences between the dust exposure level and the polymorphisms of HSP70-1, HSP70-2 and HSP70-hom in individuals. However, there were significant differences in the distribution of the G allele for HSP70-2 among the different categories of CWP and in the genotype frequency for HSP70-hom between CWP patients and controls. Furthermore, five HSP haplotypes of the HSP70 genes (namely GAT, GAC, GGT, CAC and CGT) were examined and the frequencies of haplotypes GAT and GGT were significantly higher in the CWP than in the control group. CONCLUSION: The genotyping results of this study indicate that the G allele distribution of HSP70-2, the genotype frequency of HSP70-hom poly-morphisms and some haplotypes of the HSP70 genes are associated with the susceptibility to and severity of CWP, and may be involved in the pathogenesis and development of CWP in the southwestern Chinese Han population.