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Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD.

Haq, I; Lowrey, GE; Kalsheker, N; Johnson, SR; (2011) Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD. Thorax , 66 (11) pp. 970-976. 10.1136/thx.2011.159087.

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Abstract

BACKGROUND: Recent genetic and animal studies have implicated matrix metalloproteinase-12 (MMP-12) in the pathogenesis of chronic obstructive pulmonary disease (COPD). It has previously been shown that individuals homozygous for the A/A allele of rs652438 in MMP-12 are over-represented among patients with severe COPD (n=1517). A study was undertaken to examine the functional basis of these findings. METHODS: rs652438 A and G variants were generated by site-directed mutagenesis and transfected into COS7 cells where they were expressed. Casein zymography and a specific FRET activity assay were used to compare MMP-12 activity between alleles. Cell migration was examined using a transwell assay. Patients from two COPD cohorts were genotyped for rs652438 and associated with inflammatory cell number in bronchoalveolar lavage fluid (n=10) and induced sputum (n=262); the emphysema score (n=1428) was assessed by CT scanning. RESULTS: Mean MMP activity was 2.95-fold higher by zymography (p=0.0049) and 3.45-fold higher by FRET assay (p=0.0001) for the A allele than the G allele. Mean migration of COS7 cells expressing the A allele was 2.31-fold greater than for those expressing the G allele (p=0.0001). Macrophage numbers were greater in bronchoalveolar lavage fluid (1.28-fold increase, p=0.033) and induced sputum (1.58-fold increase, p=0.083) of A/A individuals compared with A/G heterozygotes. The presence of the A allele was dose-dependently associated with increased emphysema (p=0.016). CONCLUSIONS: The rs652438 SNP alters MMP-12 activity with the A allele being more active, which is associated with increased macrophage infiltration and emphysema in the lungs of patients with COPD. These findings further implicate MMP-12 and this SNP in COPD.

Type: Article
Title: Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD.
Location: England
DOI: 10.1136/thx.2011.159087
Keywords: Adult, Aged, Aged, 80 and over, Animals, Bronchoalveolar Lavage Fluid, COS Cells, Cell Survival, Cercopithecus aethiops, Chemotaxis, Cohort Studies, Female, Gene Expression Regulation, Enzymologic, Genetic Predisposition to Disease, Humans, Male, Matrix Metalloproteinase 12, Middle Aged, Mutagenesis, Site-Directed, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Sputum, Transfection
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1431722
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