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Georgakis, M.K.* ; Malik, R.* ; Björkbacka, H.* ; Pana, T.A.* ; Demissie, S.* ; Ayers, C.* ; Elhadad, M.A. ; Fornage, M.* ; Beiser, A.S.* ; Benjamin, E.J.* ; Boekholdt, M.S.* ; Engström, G.* ; Herder, C.* ; Hoogeveen, R.C.* ; Koenig, W.* ; Melander, O.* ; Orho-Melander, M.* ; Schiopu, A.* ; Söderholm, M.* ; Wareham, N.* ; Ballantyne, C.M.* ; Peters, A. ; Seshadri, S.* ; Myint, P.K.* ; Nilsson, J.* ; de Lemos, J.A.* ; Dichgans, M.*

Circulating monocyte chemoattractant protein-1 and risk of stroke meta-analysis of population-based studies involving 17 180 individuals.

Circ. Res. 125, 773-782 (2019)

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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7 +/- 8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations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