Influence of matrix metalloproteinase-12 on fibrinogen level

• Published in: Atherosclerosis 2012-02, Vol.220 (2), p.351-354
• Main Authors: Motterle, Anna, Xiao, Qingzhong, Kiechl, Stefan, Pender, Sylvia L.F, Morris, Gareth E, Willeit, Johann, Caulfield, Mark J, Ye, Shu
• Format: Article
• Language: English
• Subjects: alleles; Animals; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - enzymology; Atherosclerosis - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Coronary heart disease; England; Fibrinogen; Fibrinogen - metabolism; Gene Frequency; genetic polymorphism; Genetic Predisposition to Disease; Heart; homozygosity; Homozygote; Humans; in vitro studies; Italy; Linear Models; Linkage Disequilibrium; Logistic Models; Matrix Metalloproteinase 12 - deficiency; Matrix Metalloproteinase 12 - genetics; Matrix Metalloproteinase 12 - metabolism; Matrix metalloproteinase-12; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial infarction; Myocardial Infarction - enzymology; Myocardial Infarction - genetics; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; risk; Risk Assessment; Risk Factors; vascular tissues
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.11.003

Abstract In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was approximately 10-fold higher in MMP12 knockout mice than wildtype mice ( p = 0.0006). Differential allelic expression analysis of human MMP12 gene polymorphism rs17368582 in human vascular tissues showed an allele-specific effect on MMP12 expression, with one allele (T) having 1.6 fold higher expression level than the other allele (C) ( p = 0.0006). In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95 mg/mL compared with 2.61 mg/mL in other individuals, p = 0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9–20.8), p = 0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7–18.3), p = 0.005]. In summary, our study in mouse and humans provides in vivo evidence of an effect of MMP12 on fibrinogen level.