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Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: A Meta-Analysis of Population-Based Studies Involving 17,180 Individuals.

Circ Res. 2019 Sep 3. doi: 10.1161/CIRCRESAHA.119.315380. [Epub ahead of print]

Authors/Editors: Georgakis MK, Malik R, Björkbacka H, Pana TA, Demissie S, Ayers C, Elhadad MA, Fornage M, Beiser AS, Benjamin EJ, Boekholdt MS, Engström G, Herder C, Hoogeveen RC, Koenig W, Melander O, Orho-Melander M, Schiopu A, Söderholm M, Wareham N, Ballantyne CM, Peters A, Seshadri S, Myint PK, Nilsson J, de Lemos JA, Dichgans M.
Publication Date: 2019

Abstract

Rationale: Pro-inflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking.

Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population.

Methods and Results: We used previously unpublished data on 17,180 stroke-free individuals (mean age 56.7{plus minus}8.1 years; 48.8% males) from six population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke over a mean follow-up interval of 16.3 years (280,522 person-years at risk; 1,435 incident stroke events). We applied Cox proportional hazard models and pooled hazard ratios (HR) using random-effects meta-analyses. Following adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1 SD increment in ln-transformed MCP-1: 1.07, 95%CI: 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR: 1.11, [1.02-1.21]), but not hemorrhagic stroke (HR: 1.02, [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared to the 1st quartile (HRs: 2nd quartile: 1.19 [1.00-1.42]; 3rd quartile: 1.35, [1.14-1.59]; 4th quartile: 1.38, [1.07-1.77]). There was no indication for heterogeneity across studies and in a sub-sample of four studies (12,516 individuals) the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein.

Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1-signaling might represent a therapeutic target to lower stroke risk.

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