Gene-environment interaction between the MMP9 C-1562T promoter variant and cigarette smoke in the pathogenesis of chronic obstructive pulmonary disease.
The aetiology of chronic obstructive pulmonary disease (COPD) is complex. While cigarette smoking is a well-established cause of COPD, a myriad of assessed genetic factors has given conflicting data. Since gene-environment interactions are thought to be implicated in aetiopathogenesis of COPD, we aimed to examine the matrix metalloproteinase (MMP) 9 C-1562T (rs3918242) functional variant and cigarette smoke in the pathogenesis of this disease. The distribution of the MMP9 C-1562T variant was analyzed in COPD patients and controls with normal pulmonary function from Serbia. Interaction between the C-1562T genetic variant and cigarette smoking was assessed using a case-control model. The response of the C-1562T promoter variant to cigarette smoke condensate (CSC) exposure was examined using a dual luciferase reporter assay. The frequency of T allele carriers was higher in the COPD group than in smoker controls (38.4% vs. 20%; OR = 2.7, P = 0.027). Interaction between the T allele and cigarette smoking was identified in COPD occurrence (OR = 4.38, P = 0.005) and severity (P = 0.001). A functional analysis of the C-1562T variant demonstrated a dose-dependent and allele-specific response (P < 0.01) to CSC. Significantly higher MMP9 promoter activity following CSC exposure was found for the promoter harboring the T allele compared to the promoter harboring the C allele (P < 0.05). Our study is the first to reveal an interaction between the MMP9-1562T allele and cigarette smoke in COPD, emphasising gene-environment interactions as a possible cause of lung damage in the pathogenesis of COPD. Environ. Mol. Mutagen. 57:447-454, 2016. © 2016 Wiley Periodicals, Inc.
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Marija
M
Stankovic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Snezana
S
Kojic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Valentina
V
Djordjevic
Oncology Region Europe, Novartis Pharma AG, Basel, Switzerland.
Andrija
A
Tomovic
Faculty of Medicine, University of Belgrade, Belgrade, Serbia.|Clinic of Pulmonology, Clinical Centre of Serbia, Belgrade, Serbia.
Ljudmila
L
Nagorni-Obradovic
Department of Pulmonology, Zvezdara University Medical Centre, Belgrade, Serbia.|School of Dentistry, Department of Internal Medicine, University of Belgrade, Belgrade, Serbia.
Natasa
N
Petrovic-Stanojevic
Faculty of Medicine, University of Belgrade, Belgrade, Serbia.|Clinic of Pulmonology, Clinical Centre of Serbia, Belgrade, Serbia.
Marija
M
Mitic-Milikic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Dragica
D
Radojkovic
D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D020298:U937 Cells
C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
MMP9; cigarette smoke; gene-environment interaction; lung disease