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

• Published in: Occupational and environmental medicine (London, England) England), 2019-03, Vol.76 (3), p.169-174
• Main Authors: Chu, Minjie, Wu, Shuangshuang, Wang, Wei, Yu, Yuhui, Zhang, Mingjiong, Sang, Lingli, Tian, Tian, Lu, Yihua, Yuan, Weiwei, Huang, Qiqing, Yi, Min, Gao, Yuexia, Xiao, Jing, Lian, Yulong, Zhuang, Xun, Zhang, Zuo-Feng, Wu, Jianqing
• Format: Article
• Language: English
• Subjects: Alleles; Blood; Carboxypeptidase M; Case studies; Case-Control Studies; China; Chromosome 12; cpm; Dust; Dust control; expression; Gene expression; Gene polymorphism; Genes; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Geriatrics; GPI-Linked Proteins - genetics; Health care; Health risk assessment; Humans; Inflammation; Leukocytes; Logistic Models; Metalloendopeptidases - genetics; mRNA; Occupational diseases; Occupational Exposure - adverse effects; ORIGINAL ARTICLE; Peripheral blood; Pneumoconiosis; Pneumoconiosis - etiology; Pneumoconiosis - genetics; Polyadenylation; Polymorphism; Polymorphism, Single Nucleotide; Public health; Reporter gene; Silica; Silicon dioxide; Silicon Dioxide - toxicity; Silicosis; Single-nucleotide polymorphism; Workers; Workplace; X-rays
• ISSN: 1351-0711; 1470-7926
• DOI: 10.1136/oemed-2018-105545

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