BACKGROUND: Ischaemic stroke and coronary heart disease are important 
contributors to the global disease burden and share atherosclerosis as the main 
underlying cause. Recent evidence from a genome-wide association study (GWAS) 
suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at 
chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we 
evaluated and extended these results by examining the relationship between MMP12 
and atherosclerosis in clinical and experimental studies.
METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 
3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink 
ProSeek CVD I array. The plasma MMP12 concentration showed association with 
incident cardiovascular and cerebrovascular events (130 and 67 events, 
respectively, over 36 months) and carotid intima-media thickness progression (P 
= 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs 
rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated 
with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA 
levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 
transcriptomic and proteomic levels were strongly significantly increased in 
carotid plaques compared with control arterial tissue and in plaques from 
symptomatic versus asymptomatic patients. By combining immunohistochemistry and 
proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + 
macrophages and interacts with elastin in plaques. MMP12 silencing in human 
THP-1-derived macrophages resulted in reduced macrophage migration.
CONCLUSIONS: Our study supports the notion that MMP12 is implicated in 
large-artery atherosclerotic stroke, functionally by enhancing elastin 
degradation and macrophage invasion in plaques.