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  Wareham; Christie M.  Ballantyne; Annette Peters; Sudha Seshadri; Phyo Kyaw Myint; Jan Nilsson; James A.  de Lemos; Martin Dichgans

doi:10.1161/CIRCRESAHA.119.315380

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)

^*Corresponding author for this work

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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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations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 language	English
Pages (from-to)	773-782
Number of pages	10
Journal	Circulation Research
Volume	125
Issue number	8
Early online date	3 Sept 2019
DOIs	https://doi.org/10.1161/CIRCRESAHA.119.315380
Publication status	Published - 27 Sept 2019

Bibliographical note

M. Georgakis is funded by scholarships from the German Academic Exchange Service (DAAD) and Onassis Foundation. The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The DHS study was funded by a grant from the Donald W. Reynolds Foundation. The EPIC-Norfolk study is funded by grants from the Medical Research Council UK (G9502233, G0401527) and Cancer Research UK (C864/A8257, C864/A2883). FHS is supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and No. HHSN268201500001I and 75N92019D00031), received funding by grants from the National Institute of Aging (R01s AG054076, AG049607, AG059421, U01-AG049505, AG058589 and AG052409) and the National Institute of Neurological Disorders and Stroke (R01 NS017950, UH2 NS100605), as well as grants for the MCP-1 measurements by NIH (1RO1 HL64753, R01 HL076784, 1 R01 AG028321). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The MDCS-CV study has been supported with funding from the Swedish Research Council, Swedish Heart and Lung Foundations, and the Swedish Foundation for Strategic Research. This project has received funding from the European Union’s Horizon 2020 research and innovation programme (No 666881), SVDs@target (to M. Dichgans) and No 667375, CoSTREAM (to M. Dichgans); the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and the CRC 1123 (B3) (to M. Dichgans); the Corona Foundation (to M. Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)(to M. Dichgans); the e:Med program (e:AtheroSysMed) (to M. Dichgans) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456) (to M. Dichgans).
The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Keywords

monocyte chemoattractant protein-1
CCL2
stroke
cerebrovascular disease
atherosclerosis

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Cite this

Georgakis, M. K., Malik, R., Björkbacka, H., Pana, T. A., Demissie, S., Ayers, C., Elhadad, M. A., Fornage, M., Beiser, A., Benjamin, E. J., Boekholdt, S. M., Engström, G., Herder, C., Hoogeveen, R. C., Koenig, W., Melander, O., Orho-Melander, M., Schiopu, A., Söderholm, M., ... Dichgans, M. (2019). Circulating monocyte chemoattractant protein-1 and risk of stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals. Circulation Research, 125(8), 773-782. https://doi.org/10.1161/CIRCRESAHA.119.315380

Georgakis, MK, Malik, R, Björkbacka, H, Pana, TA, Demissie, S, Ayers, C, Elhadad, MA, Fornage, M, Beiser, A, Benjamin, EJ, Boekholdt, SM, 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

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

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 = "monocyte chemoattractant protein-1, CCL2, stroke, cerebrovascular disease, atherosclerosis",

author = "Georgakis, {Marios K.} and Rainer Malik and Harry Bj{\"o}rkbacka and Pana, {Tiberiu A} and Serkalem Demissie and Colby Ayers and Elhadad, {Mohamed A.} and Myriam Fornage and Alexa Beiser and Benjamin, {Emelia J.} and Boekholdt, {S Matthijs} 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 Kyaw} and Jan Nilsson and {de Lemos}, {James A.} and Martin Dichgans",

note = "M. Georgakis is funded by scholarships from the German Academic Exchange Service (DAAD) and Onassis Foundation. The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The DHS study was funded by a grant from the Donald W. Reynolds Foundation. The EPIC-Norfolk study is funded by grants from the Medical Research Council UK (G9502233, G0401527) and Cancer Research UK (C864/A8257, C864/A2883). FHS is supported by the National Heart, Lung and Blood Institute{\textquoteright}s Framingham Heart Study (Contract No. N01-HC-25195 and No. HHSN268201500001I and 75N92019D00031), received funding by grants from the National Institute of Aging (R01s AG054076, AG049607, AG059421, U01-AG049505, AG058589 and AG052409) and the National Institute of Neurological Disorders and Stroke (R01 NS017950, UH2 NS100605), as well as grants for the MCP-1 measurements by NIH (1RO1 HL64753, R01 HL076784, 1 R01 AG028321). The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit{\"a}t, as part of LMUinnovativ. The MDCS-CV study has been supported with funding from the Swedish Research Council, Swedish Heart and Lung Foundations, and the Swedish Foundation for Strategic Research. This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme (No 666881), SVDs@target (to M. Dichgans) and No 667375, CoSTREAM (to M. Dichgans); the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and the CRC 1123 (B3) (to M. Dichgans); the Corona Foundation (to M. Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)(to M. Dichgans); the e:Med program (e:AtheroSysMed) (to M. Dichgans) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456) (to M. Dichgans). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. ",

year = "2019",

month = sep,

day = "27",

doi = "10.1161/CIRCRESAHA.119.315380",

language = "English",

volume = "125",

pages = "773--782",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

number = "8",

}

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 A

AU - Demissie, Serkalem

AU - Ayers, Colby

AU - Elhadad, Mohamed A.

AU - Fornage, Myriam

AU - Beiser, Alexa

AU - Benjamin, Emelia J.

AU - Boekholdt, S Matthijs

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 Kyaw

AU - Nilsson, Jan

AU - de Lemos, James A.

AU - Dichgans, Martin

N1 - M. Georgakis is funded by scholarships from the German Academic Exchange Service (DAAD) and Onassis Foundation. The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The DHS study was funded by a grant from the Donald W. Reynolds Foundation. The EPIC-Norfolk study is funded by grants from the Medical Research Council UK (G9502233, G0401527) and Cancer Research UK (C864/A8257, C864/A2883). FHS is supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and No. HHSN268201500001I and 75N92019D00031), received funding by grants from the National Institute of Aging (R01s AG054076, AG049607, AG059421, U01-AG049505, AG058589 and AG052409) and the National Institute of Neurological Disorders and Stroke (R01 NS017950, UH2 NS100605), as well as grants for the MCP-1 measurements by NIH (1RO1 HL64753, R01 HL076784, 1 R01 AG028321). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The MDCS-CV study has been supported with funding from the Swedish Research Council, Swedish Heart and Lung Foundations, and the Swedish Foundation for Strategic Research. This project has received funding from the European Union’s Horizon 2020 research and innovation programme (No 666881), SVDs@target (to M. Dichgans) and No 667375, CoSTREAM (to M. Dichgans); the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and the CRC 1123 (B3) (to M. Dichgans); the Corona Foundation (to M. Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)(to M. Dichgans); the e:Med program (e:AtheroSysMed) (to M. Dichgans) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456) (to M. Dichgans). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

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 - monocyte chemoattractant protein-1

KW - CCL2

KW - stroke

KW - cerebrovascular disease

KW - atherosclerosis

UR - http://www.mendeley.com/research/circulating-monocyte-chemoattractant-protein1-risk-stroke-metaanalysis-populationbased-studies-invol

U2 - 10.1161/CIRCRESAHA.119.315380

DO - 10.1161/CIRCRESAHA.119.315380

M3 - Article

C2 - 31476962

SN - 0009-7330

VL - 125

SP - 773

EP - 782

JO - Circulation Research

JF - Circulation Research

IS - 8

ER -

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

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

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