TY - JOUR
T1 - Circulating monocyte chemoattractant protein-1 and risk of stroke meta-analysis of population-based studies involving 17180 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 - Matthijs Boekholdt, 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
N1 - Funding Information:
M.K. Georgakis is funded by scholarships from the German Academic Exchange Service and Onassis Foundation. The ARIC study (Atherosclerosis Risk in Communities Study) has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Department of Health and Human Services, under contract No. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. The DHS (Dallas Heart Study) was funded by a grant from the Donald W. Reynolds Foundation. The EPIC-Norfolk study (Norfolk Arm of the European Prospective Investigation of Cancer) is funded by grants from the Medical Research Council UK (G9502233 and G0401527) and Cancer Research UK (C864/A8257 and C864/A2883). FHS (Framingham Heart Study) is supported by the National Heart, Lung and Blood Institute Framing-ham Heart Study (contract No. N01-HC-25195, 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 and UH2 NS100605), as well as grants for the MCP-1 (monocyte chemoattractant protein-1) measurements by NIH (1RO1 HL64753, R01 HL076784, and 1 R01 AG028321). The KORA study (Kooperative Gesundheits-forschung in der Region Augsburg) 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 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 (Malmö Diet and Cancer Study–Cardiovascular Subcohort) 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 (Common Mechanisms and Pathways in Stroke and Alzheimer's Disease; to M. Dichgans); the DFG (Deutsche Forschungsgemeinschaft) 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 No. 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.
Funding Information:
J.A. de Lemos reports research grants from Abbott Diagnostics and Roche Diagnostics, consulting from Ortho Clinical Diagnostics and Jannsen, honoraria for steering committee membership from Amgen, and DSMB (Data and Safety Monitoring Board) membership from Novo Nordisc and Regeneron. W. Koenig reports personal fees for consulting from AstraZeneca, Novartis, DalCor, Kowa, Amgen, and Sanofi and grants and nonfinancial support from Roche Diagnostics, Beckmann, Singulex, and Abbott. C. Ayers reports statistical consulting fees from the National Institutes of Health. R.C. Hoogeveen reports research grants and personal fees for consulting from Denka Seiken. The other authors report no conflicts.
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 17180 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 (280522 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 (12516 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 17180 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 (280522 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 (12516 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
UR - http://www.scopus.com/inward/record.url?scp=85072718369&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072718369&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.119.315380
DO - 10.1161/CIRCRESAHA.119.315380
M3 - Article
C2 - 31476962
AN - SCOPUS:85072718369
VL - 125
SP - 773
EP - 782
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 8
ER -