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

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Original article
Functional variant of the carboxypeptidase M (CPM) gene may affect silica-related pneumoconiosis susceptibility by its expression: a multistage case–control study
  1. Minjie Chu1,2,
  2. Shuangshuang Wu3,
  3. Wei Wang4,
  4. Yuhui Yu1,
  5. Mingjiong Zhang3,
  6. Lingli Sang1,
  7. Tian Tian1,
  8. Yihua Lu1,
  9. Weiwei Yuan3,
  10. Qiqing Huang3,
  11. Min Yi1,
  12. Yuexia Gao1,
  13. Jing Xiao1,
  14. Yulong Lian1,
  15. Xun Zhuang1,
  16. Zuo-Feng Zhang2,
  17. Jianqing Wu3
  1. 1 Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
  2. 2 Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA
  3. 3 Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
  4. 4 Department of Occupational Health, Center for Disease Control and Prevention of Wuxi, Wuxi, China
  1. Correspondence to Professor Zuo-Feng Zhang, Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA ; zfzhang{at}ucla.edu and Professor Jianqing Wu, Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China ; jwuny{at}njmu.edu.cn

Abstract

Objectives In 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.

Methods We 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.

Results We 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.

Conclusions The 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.

  • silicosis
  • cpm
  • expression

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/oemed-2018-105545

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    Footnotes

    • MC, SW, WW and YY contributed equally.

    • Contributors Study design was led by XZ, Z-FZ and JW, with contributions from WW, YY, MZ, LS, TT, YL, WY, QH and MY carried out enrolment of participants and collection of human samples. Data collection was carried out by WW, YY, MZ and LS. Statistical analyses were conducted by YG, JX and YL. MC and SW drafted the manuscript. All authors participated in data analysis, critically revised the manuscript and approved the final version.

    • Funding The funding sources had no role to play in the study design, the collection and interpretation of the data, writing of the report or decision to submit this paper for publication.

    • Competing interests None declared.

    • Ethics approval Ethics Committee of the Affiliated Hospital of Nantong University.

    • Provenance and peer review Not commissioned; externally peer reviewed.