Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD. Issue 11 (5th July 2011)

• Record Type: Journal Article
• Authors: Haq, Imran; Lowrey, Gillian E; Kalsheker, Noor; Johnson, Simon R
• Is Part Of: Thorax. Volume 66:Issue 11(2011)
• Page Start: 970
• Page End: 976
• Publication Date: 2011-07-05
• Subjects: rs652438 -- matrix metalloproteinase -- 1082A/G -- 357Asn/Ser -- emphysema -- COPD mechanisms -- emphysema -- macrophage biology; Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thx.2011.159087
• Languages: English
• ISSNs: 0040-6376

Abstract

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.