A protective polymorphism inMMP16, improved blood gas levels, and chronic obstructive pulmonary diseases: Family and two population‐based studies
- 20 March 2020
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 41 (7), 1280-1297
- https://doi.org/10.1002/humu.24013
Abstract
The aberrant expression of matrix metalloproteinases (MMPs) is known to contribute to the pathogenesis of airway remodeling and alveolar disruption in chronic obstructive pulmonary disease (COPD). In the discovery stage, 11 COPD from five families were subjected to whole‐genome sequencing (WGS), and 21 common polymorphisms in MMPs and TIMPs were identified. These polymorphisms were genotyped in two subsequent verification studies. Of these polymorphisms, c.2392G>A (rs2664370T>C)and c.4158C>A (rs2664369T>G) in MMP16 remained significantly different. Functionally, we found that MMP16 expression was significantly increased in peripheral blood monocytes (PBMCs) from COPD and in cigarette smoke extract (CSE)‐treated 16HBE cells compared to controls. This was also shown by bioinformatic analysis. COPD carrying rs2664370CC showed decreased levels of MMP16 in the plasma and in PBMCs compared to those carrying CT and TT. Treatment with hsa‐miR‐576‐5p mimics led to a greater reduction in luciferase reporter activity in cells transfected with rs2664370CC. Moreover, blood levels of base excess, PCO2, and PO2 in COPD with rs2664370CC were significantly lower than those with rs2664370CT+TT. Taken together, these results demonstrate that the rs2664370T>C polymorphism in MMP16 protects against the risk of COPD, likely by favoring an interaction with hsa‐miR‐576‐5p, leading to reduced MMP16 expression and improved blood gas levels.Funding Information
- National Natural Science Foundation of China (81520108001, 81220108001, 81770043, 81700043)
This publication has 37 references indexed in Scilit:
- Genome‐wide association study validation identifies novel loci for atherosclerotic cardiovascular diseaseJournal of Thrombosis and Haemostasis, 2012
- Lymphoid enhancer-binding factor 1, a representative of vertebrate-specific Lef1/Tcf1 sub-family, is a Wnt-beta-catenin pathway target gene in human endothelial cells which regulates matrix metalloproteinase-2 expression and promotes endothelial cell invasionVascular Cell, 2011
- A functional polymorphism in MMP1 could influence osteomyelitis developmentJournal of Bone and Mineral Research, 2010
- Genetic polymorphisms of matrix metalloproteinases and their inhibitors in potentially malignant and malignant lesions of the head and neckJournal of Biomedical Science, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancerOral Oncology, 2009
- A distribution free summarization method for Affymetrix GeneChip® arraysBioinformatics, 2006
- Up-regulation of Expression of the Ubiquitin Carboxyl-Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette SmokersCancer Research, 2006
- The Structure of Haplotype Blocks in the Human GenomeScience, 2002
- A new look at the statistical model identificationIEEE Transactions on Automatic Control, 1974