Genome-wide Analysis of Circulating Matrix Metalloproteinase 8 Levels

Objectives: Enhanced expression and activation of matrix metalloproteinase 8 (MMP-8) is a key factor responsible for tissue degradation during periodontitis. Patients with chronic periodontitis display elevated serum and plasma concentrations of MMP-8. Serum MMP-8 is also associated with the presence and outcome of cardiovascular diseases. The origin of circulating MMP-8 is not completely clear.
Methods: We performed a genome-wide association study in two populations comprising altogether 6049 individuals to identify genetic factors contributing to serum MMP-8 levels. To clarify the molecular mechanisms behind elevated MMP-8, we performed functional experiments with isolated human neutrophils. Moreover, we studied if MMP-8-associated variants are linked to increased risk of cardiovascular diseases and overall mortality in over 20’000 subjects.
Results: The strongest association with serum MMP-8 was found in locus 1q31.1, containing the gene complement factor H [lead SNP: rs800292, beta (SD) -0.24 (0.02), p = 2.4 * 10^-35 for log-transformed MMP-8]. Another association was detected in the S100A9-S100A12-S100A8 region in 1q21.3 [strongest association: rs1560833, beta (SD) -0.17 (0.02), p = 5.3 * 10^-15]. Rs1560833 was associated also with plasma MMP-8, while rs800292 was not. In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele led to decreased release of MMP-8 from neutrophils. The minor allele of rs1560833 was also associated with cardiovascular disease [OR (95% CI): 0.90 (0.82 – 0.99), p = 0.032] in men, but not in women.
Conclusions: In conclusion, the complement system strongly contributes to serum MMP-8. Polymorphism in S100A9 affects both serum and plasma MMP-8, and is associated with an increased risk of cardiovascular diseases. These findings enable the identification of individuals with genetic predisposition to higher release of MMP-8, and highlight the link between inflammation, such as periodontitis, and immune system and cardiovascular diseases.