Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke: A Mendelian Randomization Study

Jara Cárcel-Márquez, Natalia Cullell, Elena Muiño, Cristina Gallego-Fabrega, Miquel Lledós, Laura Ibañez, Jerzy Krupinski, Joan Montaner, Carlos Cruchaga, Jin Moo Lee, Dipender Gill, Guillaume Paré, Marina Mola-Caminal, Jaume Roquer, Jordi Jimenez-Conde, Joan Martí-Fàbregas, Israel Fernandez-Cadenas

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background and Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain. Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791). Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86-0.94]; q value=7.43×10-5), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92-0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65-0.77]; q value=5.11×10-14); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06-1.45]; q value=0.03). No associations were found in relation to stroke outcome. Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

Original languageEnglish
Pages (from-to)E316-E320
Issue number7
StatePublished - Jul 1 2021


  • atherosclerosis
  • ischemic stroke
  • metalloproteinase
  • modified Rankin Scale
  • risk factor


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