State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangdong, Guangzhou, China.
Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona, Tucson, Arizona.
Hum Mutat. 2020 Jul;41(7):1280-1297. doi: 10.1002/humu.24013. Epub 2020 Apr 14.
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 , and PO 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.
基质金属蛋白酶（MMPs）的异常表达被认为有助于慢性阻塞性肺疾病（COPD）气道重塑和肺泡破坏的发病机制。在发现阶段，对来自五个家庭的 11 名 COPD 患者进行了全基因组测序，并鉴定了 MMPs 和 TIMPs 中的 21 个常见多态性。这些多态性在随后的两项验证研究中进行了基因分型。在这些多态性中，MMP16 中的 c.2392G>A（rs2664370T>C）和 c.4158C>A（rs2664369T>G）仍然存在显著差异。功能上，我们发现与对照组相比，COPD 患者的外周血单核细胞（PBMC）和香烟烟雾提取物处理的 16HBE 细胞中 MMP16 的表达显著增加。生物信息学分析也证实了这一点。与携带 CT 和 TT 的个体相比，携带 rs2664370CC 的 COPD 患者的血浆和 PBMC 中 MMP16 的水平降低。用 hsa-miR-576-5p 模拟物处理后，rs2664370CC 转染的细胞中的荧光素酶报告基因活性降低更为显著。此外，携带 rs2664370CC 的 COPD 患者的血 base excess、PCO 和 PO 水平明显低于携带 rs2664370CT+TT 的患者。综上所述，这些结果表明 MMP16 中的 rs2664370T>C 多态性降低了 COPD 的发病风险，可能是通过促进与 hsa-miR-576-5p 的相互作用，导致 MMP16 表达降低和血气水平改善。
