Functional variant of the carboxypeptidase M (CPM) gene may affect silica-related pneumoconiosis susceptibility by its expression: a multistage case–control study

Abstract

ObjectivesIn a genome-wide association study, we discovered chromosome 12q15 (defined as rs73329476) as a silica-related pneumoconiosis susceptibility region. However, the causal variants in this region have not yet been reported.MethodsWe systematically screened eight potentially functional single-neucleotide polymorphism (SNPs) in the genes near rs73329476 (carboxypeptidase M (CPM) and cleavage and polyadenylation specific factor 6 (CPSF6)) in a case–control study including 177 cases with silicosis and 204 healthy controls, matched to cases with years of silica dust exposure. We evaluated the associations between these eight SNPs and the development of silicosis. Luciferase reporter gene assays were performed to test the effects of selected SNP on the activity of CPM in the promoter. In addition, a two-stage case–control study was performed to investigate the expression differences of the two genes in peripheral blood leucocytes from a total of 64 cases with silicosis and 64 healthy controls with similar years of silica dust exposure as the cases.ResultsWe found a strong association between the mutant rs12812500 G allele and the susceptibility of silicosis (OR=1.45, 95% CI 1.03 to 2.04, p=0.034), while luciferase reporter gene assays indicated that the mutant G allele of rs12812500 is strongly associated with increased luciferase levels compared with the wild-type C allele (p<0.01). Moreover, the mRNA (peripheral blood leucocytes) expression of the CPM gene was significantly higher in subjects with silicosis compared with healthy controls.ConclusionsThe rs12812500 variant of the CPM gene may increase silicosis susceptibility by affecting the expression of CPM, which may contribute to silicosis susceptibility with biological plausibility.

miRNA sequencing reveals miRNA‐4508 from peripheral blood lymphocytes as potential diagnostic biomarker for silica‐related pulmonary fibrosis: A multistage study

“…The characteristics of the 177 SPF cases and 204 healthy workers recruited from Wuxi who were exposed to silica dust are entirely consistent with those of our previously published studies . Additional 126 SPF cases were recruited in 2017 from Datun Mining Business Group Co. Ltd. of Xuzhou in Jiangsu Province, with 126 healthy worker controls randomly selected from a pool of >1000 individuals with occupational dust exposure who participated in the routine health surveillance in 2017 in Xuzhou.…”

The rs74794265 SNP of the SREK1 Gene is Associated with COPD in Kashi, China

“…In addition, silicosis, which is a chronic progressive fibrotic lung inflammation, may increase the risk of COPD. Research indicates that the functional variant of the CPM gene 16 and the rs2609255 polymorphism in the FAM13A gene 17 are associated with silicosis susceptibility in a Chinese population. In our study, we discussed the susceptibility of SREK1 rs74794265 C>T polymorphism in COPD.…”

Pneumoconiosis: current status and future prospects

“…Genomics studies on silicosis suggest that single nucleotide polymorphisms are associated with susceptibility to pneumoconiosis and several disease-related single nucleotide polymorphisms have been found ( eg , rs73329476, rs12812500). [ 60 ] Epigenomics studies have shown that some miRNAs are closely associated with pneumoconiosis risk and disease progression, and have the potential to serve as non-invasive biomarkers and prognostic markers for early pneumoconiosis. [ 61 , 62 ] Transcriptomics and proteomics identify a range of differentially expressed protein-coding genes and proteins.…”