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 Alexandru Pana, Serkalem Demissie, Colby Ayers, Mohamed A. Elhadad, Myriam Fornage, Alexa S. Beiser, Emelia J. Benjamin, Matthijs S. 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 K. Myint, Jan Nilsson, James A. de Lemos, Martin Dichgans

Research output: Contribution to journalArticle

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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations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 (US)
Pages (from-to)773-782
Number of pages10
JournalCirculation research
Volume125
Issue number8
DOIs
StatePublished - Sep 27 2019

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Chemokine CCL2
Meta-Analysis
Stroke
Population
Random Allocation
Proportional Hazards Models
C-Reactive Protein
Observational Studies
Blood Vessels
Interleukin-6
Atherosclerosis

Keywords

  • atherosclerosis
  • cerebrovascular disorders
  • chemokine CCL2
  • inflammation
  • stroke

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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

In: Circulation research, Vol. 125, No. 8, 27.09.2019, p. 773-782.

Research output: Contribution to journalArticle

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 2019, 'Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals', Circulation research, vol. 125, no. 8, pp. 773-782. https://doi.org/10.1161/CIRCRESAHA.119.315380
Georgakis, Marios K. ; Malik, Rainer ; Björkbacka, Harry ; Pana, Tiberiu Alexandru ; Demissie, Serkalem ; Ayers, Colby ; Elhadad, Mohamed A. ; Fornage, Myriam ; Beiser, Alexa S. ; Benjamin, Emelia J. ; Boekholdt, Matthijs S. ; Engström, Gunnar ; Herder, Christian ; Hoogeveen, Ron C. ; Koenig, Wolfgang ; Melander, Olle ; Orho-Melander, Marju ; Schiopu, Alexandru ; Söderholm, Martin ; Wareham, Nick ; Ballantyne, Christie M. ; Peters, Annette ; Seshadri, Sudha ; Myint, Phyo K. ; Nilsson, Jan ; de Lemos, James A. ; Dichgans, Martin. / Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke : Meta-Analysis of Population-Based Studies Involving 17 180 Individuals. In: Circulation research. 2019 ; Vol. 125, No. 8. pp. 773-782.
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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.",
keywords = "atherosclerosis, cerebrovascular disorders, chemokine CCL2, inflammation, stroke",
author = "Georgakis, {Marios K.} and Rainer Malik and Harry Bj{\"o}rkbacka and Pana, {Tiberiu Alexandru} and Serkalem Demissie and Colby Ayers and Elhadad, {Mohamed A.} and Myriam Fornage and Beiser, {Alexa S.} and Benjamin, {Emelia J.} and Boekholdt, {Matthijs S.} and Gunnar Engstr{\"o}m and Christian Herder and Hoogeveen, {Ron C.} and Wolfgang Koenig and Olle Melander and Marju Orho-Melander and Alexandru Schiopu and Martin S{\"o}derholm and Nick Wareham and Ballantyne, {Christie M.} and Annette Peters and Sudha Seshadri and Myint, {Phyo K.} and Jan Nilsson and {de Lemos}, {James A.} and Martin Dichgans",
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TY - JOUR

T1 - Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke

T2 - Meta-Analysis of Population-Based Studies Involving 17 180 Individuals

AU - Georgakis, Marios K.

AU - Malik, Rainer

AU - Björkbacka, Harry

AU - Pana, Tiberiu Alexandru

AU - Demissie, Serkalem

AU - Ayers, Colby

AU - Elhadad, Mohamed A.

AU - Fornage, Myriam

AU - Beiser, Alexa S.

AU - Benjamin, Emelia J.

AU - Boekholdt, Matthijs S.

AU - Engström, Gunnar

AU - Herder, Christian

AU - Hoogeveen, Ron C.

AU - Koenig, Wolfgang

AU - Melander, Olle

AU - Orho-Melander, Marju

AU - Schiopu, Alexandru

AU - Söderholm, Martin

AU - Wareham, Nick

AU - Ballantyne, Christie M.

AU - Peters, Annette

AU - Seshadri, Sudha

AU - Myint, Phyo K.

AU - Nilsson, Jan

AU - de Lemos, James A.

AU - Dichgans, Martin

PY - 2019/9/27

Y1 - 2019/9/27

N2 - 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.

AB - 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.

KW - atherosclerosis

KW - cerebrovascular disorders

KW - chemokine CCL2

KW - inflammation

KW - stroke

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