Abstract
ObjectiveTo evaluate the association between single-nucleotide polymorphisms (SNPs) in RNA-seq identified mRNAs and silicosis susceptibility.MethodsA comprehensive RNA-seq was performed to screen for differently expressed mRNAs in the peripheral blood lymphocytes of eight subjects exposed to silica dust (four silicosis cases and four healthy controls). Following this, the SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility, were screened through silicosis-related genome-wide association studies (GWAS) (155 silicosis cases and 141 healthy controls), whereas functional expression quantitative trait locus (eQTL)-SNPs were identified using the GTEx database. Finally, the association between functional eQTL-SNPs and silicosis susceptibility (194 silicosis cases and 235 healthy controls) was validated.ResultsA total of 70 differentially expressed mRNAs (fold change > 2 or fold change < 0.5, P < 0.05) was obtained using RNA-seq. Furthermore, 476 SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility (P < 0.05) were obtained using GWAS, whereas subsequent six functional eQTL-SNPs were identified. The mutant A allele of rs9273410 in HLA-DQB1 indicated a potential increase in silicosis susceptibility in the validation stage (additive model: odds ratio (OR)= 1.31, 95% confidence interval (CI) = 0.99–1.74, P = 0.061), whereas the combination of GWAS and the validation results indicated that the mutant A allele of rs9273410 was associated with increased silicosis susceptibility (additive model: OR = 1.35, 95% CI =1.09–1.68, P = 0.006).ConclusionThe mutant A allele of rs9273410 was associated with increased silicosis susceptibility by modulating the expression of HLA-DQB1.
Highlights
Silicosis is a chronic progressive fibrotic lung disease, which may lead to respiratory failure or death [1, 2]
476 SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility (P < 0.05) were obtained using genome-wide association studies (GWAS), whereas subsequent six functional expression quantitative trait locus (eQTL)-SNPs were identified
The mutant A allele of rs9273410 in HLA-DQB1 indicated a potential increase in silicosis susceptibility in the validation stage (additive model: odds ratio (OR)= 1.31, 95% confidence interval (CI) = 0.99–1.74, P = 0.061), whereas the combination of GWAS and the validation results indicated that the mutant A allele of rs9273410 was associated with increased silicosis susceptibility
Summary
Silicosis is a chronic progressive fibrotic lung disease, which may lead to respiratory failure or death [1, 2]. The Global Silicosis Elimination Plan has established the goal of reducing the impact of silicosis by 2030; silicosis remains a vital issue threatening the health of individuals in various occupations in both developing and developed countries. China records the largest incidence of silicosis in the world, with more than 873,000 silicosis cases being recorded by the end of 2018 [3]. According to the systematic analysis of the Global Burden of Disease Study in 2016, East Asia ranks first in the world for the highest silicosis fatality rate followed by Western Europe [4]. Some Australian coal mining communities are facing a severe epidemic of accelerated silicosis due to artificial stone exposure [5]. Silicosis remains a major global health concern [6]
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