Circulating monocyte chemoattractant protein-1 and risk of stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals

Marios K. Georgakis, Rainer Malik, Harry Björkbacka, Tiberiu A Pana, Serkalem Demissie, Colby Ayers, Mohamed A. Elhadad, Myriam Fornage, Alexa Beiser, Emelia J. Benjamin, S Matthijs Boekholdt, Gunnar Engström, Christian Herder, Ron C. Hoogeveen, Wolfgang Koenig, Olle Melander, Marju Orho-Melander, Alexandru Schiopu, Martin Söderholm, Nick WarehamChristie M. Ballantyne, Annette Peters, Sudha Seshadri, Phyo Kyaw Myint, Jan Nilsson, James A. de Lemos, Martin Dichgans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)
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Abstract

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After 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 with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (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.Visual Overview: An online visual overview is available for this article.

Original languageEnglish
Pages (from-to)773-782
Number of pages10
JournalCirculation Research
Volume125
Issue number8
Early online date3 Sep 2019
DOIs
Publication statusPublished - 27 Sep 2019

Keywords

  • monocyte chemoattractant protein-1
  • CCL2
  • stroke
  • cerebrovascular disease
  • atherosclerosis

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