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

• Published in: Stroke (1970) Vol. 52; no. 7; pp. e316 - e320
• Main Authors: Cárcel-Márquez, Jara, Cullell, Natalia, Muiño, Elena, Gallego-Fabrega, Cristina, Lledós, Miquel, Ibañez, Laura, Krupinski, Jerzy, Montaner, Joan, Cruchaga, Carlos, Lee, Jin-Moo, Gill, Dipender, Paré, Guillaume, Mola-Caminal, Marina, Roquer, Jaume, Jimenez-Conde, Jordi, Martí-Fàbregas, Joan, Fernandez-Cadenas, Israel
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 01.07.2021
• Subjects: Biomarkers - blood; Cohort Studies; Female; Genome-Wide Association Study - methods; Humans; Ischemic Stroke - blood; Ischemic Stroke - genetics; Male; Matrix Metalloproteinase 1 - blood; Matrix Metalloproteinase 12 - blood; Matrix Metalloproteinase 8 - blood; Mendelian Randomization Analysis - methods; atherosclerosis; modified Rankin Scale; risk factor; metalloproteinase; ischemic stroke
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/STROKEAHA.120.033041

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. 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). 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. 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.