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

Georgakis, Marios K. ; Malik, Rainer ; Björkbacka, Harry LU ; Pana, Tiberiu Alexandru ; Demissie, Serkalem ; Ayers, Colby ; Elhadad, Mohamed A. ; Fornage, Myriam ; Beiser, Alexa S. and Benjamin, Emelia J. , et al. (2019) In Circulation Research 125(8). p.773-782
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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations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... (More)

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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations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.

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publication status
published
subject
keywords
atherosclerosis, cerebrovascular disorders, chemokine CCL2, inflammation, stroke
in
Circulation Research
volume
125
issue
8
pages
10 pages
publisher
American Heart Association
external identifiers
  • pmid:31476962
  • scopus:85072718369
ISSN
0009-7330
DOI
10.1161/CIRCRESAHA.119.315380
language
English
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yes
id
2487f2ad-8be0-49c1-b3b2-9f1b72524992
date added to LUP
2019-10-10 10:55:06
date last changed
2020-01-13 02:27:30
@article{2487f2ad-8be0-49c1-b3b2-9f1b72524992,
  abstract     = {<p>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.</p>},
  author       = {Georgakis, Marios K. and Malik, Rainer and Björkbacka, Harry and Pana, Tiberiu Alexandru and Demissie, Serkalem and Ayers, Colby and Elhadad, Mohamed A. and Fornage, Myriam and Beiser, Alexa S. and Benjamin, Emelia J. and Boekholdt, Matthijs S. and Engström, Gunnar and Herder, Christian and Hoogeveen, Ron C. and Koenig, Wolfgang and Melander, Olle and Orho-Melander, Marju and Schiopu, Alexandru and Söderholm, Martin and Wareham, Nick and Ballantyne, Christie M. and Peters, Annette and Seshadri, Sudha and Myint, Phyo K. and Nilsson, Jan and de Lemos, James A. and Dichgans, Martin},
  issn         = {0009-7330},
  language     = {eng},
  number       = {8},
  pages        = {773--782},
  publisher    = {American Heart Association},
  series       = {Circulation Research},
  title        = {Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke : Meta-Analysis of Population-Based Studies Involving 17 180 Individuals},
  url          = {http://dx.doi.org/10.1161/CIRCRESAHA.119.315380},
  doi          = {10.1161/CIRCRESAHA.119.315380},
  volume       = {125},
  year         = {2019},
}