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A protective polymorphism in MMP16 , improved blood gas levels, and chronic obstructive pulmonary diseases: Family and two population‐based studies
Author(s) -
Zhang Zili,
Wang Jian,
Zheng Zeguang,
Chen Xindong,
Xu Guihua,
Chen Sifan,
Liu Fei,
Chen Lingdan,
Ding Mingjing,
Yuan Liang,
Li Yuanyuan,
Qian Jing,
Xie Xiaohui,
Deng Bingxian,
Lu Wenju
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24013
Subject(s) - copd , pathogenesis , matrix metalloproteinase , peripheral blood mononuclear cell , biology , pco2 , population , immunology , medicine , genetics , in vitro , environmental health
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, 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‐treated 16HBE cells compared with controls. This was also shown by bioinformatics analysis. COPD carrying rs2664370CC showed decreased levels of MMP16 in the plasma and in PBMCs compared with 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, PCO 2 , and PO 2 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 interaction with hsa‐miR‐576‐5p, leading to reduced MMP16 expression and improved blood gas levels.