The association at 11q22 is located in a cluster of matrix metalloproteinases including MMP12 (matrix metalloproteinase 12, also known as macrophage metalloelastase or matrix metallopeptidase 12). MMP12 is produced by macrophages and degrades elastin, and has been extensively characterized in COPD both in mouse models50 and in human studies51,52. Several studies have described genetic associations with COPD or lung function for a SNP in the promoter region of MMP12, rs2276109 [-82A→G], where the minor allele leads to decreased promoter activity through less efficient binding of AP-146,53–55. In a combined analysis of a total of 7 cohorts, including subjects with both asthma and COPD, the minor allele (G) of rs2276109 was associated with improved lung function46. Of note, two of the COPD cohorts included in this study were enriched for severe disease. Similarly, in a study of 977 European cases and 876 controls, an association was identified for a haplotype including rs2276109 in MMP12 among severe cases (P = 0•0039) 54. SNP rs626750 is in strong LD with rs2276109 (r2 = 0•63). Our study thus confirms, with the same direction of effect, these previously described associations at genome-wide significance, and supports a role for MMP12 in severe COPD.
