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 Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations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: atherosclerosis; cerebrovascular disorders; chemokine CCL2; inflammation; stroke.

Figure 1.

Cross-sectional associations between baseline circulating MCP-1 levels, demographic factors, conventional vascular risk factors, and inflammatory biomarkers. Shown are the results from the pooled sample consisting of six population-based studies. * statistically significant results (after correction for multiple comparisons statistical significance was set at p <0.05/12=0.004). ** <40 and 40-59 mg/dL for men, <50 and 50-59 mg/dL for women. Z-score for circulating MCP-1 levels correspond to differences from the mean value of each study. P-values are derived from meta-regression. Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein- 1; SBP, systolic blood pressure.

Figure 2.

Associations between baseline circulating MCP-1 levels and risk of any stroke. Shown are the results from random-effects meta-analyses of the pooled sample consisting of six population-based studies.Model 1 is adjusted for age, sex, and race. Model 2 is adjusted for age, sex, race, and vascular risk factors including body mass index (1 kg/m2 increment), smoking (current vs. non-current), estimated glomerular filtration rate (1 mL/min/1.73 m² increment), history of coronary artery disease, diabetes mellitus, hypercholesterolemia, hypertension, atrial fibrillation, and heart failure at baseline. Model 3 is additionally adjusted for circulating high-sensitivity C-reactive protein (hsCRP) levels. Analyses for 1 SD increment correspond to ln-transformed MCP-1 levels.

Figure 3.

Associations between baseline circulating MCP-1 levels and risk of (A) ischemic stroke and (B) hemorrhagic stroke. Shown are the results from random-effects meta-analyses of the pooled sample consisting of six population-based studies. * Statistical significance threshold was set at p <0.05/2=0.025 after correction for multiple comparisons (two stroke subtypes). Model 1 is adjusted for age, sex, and race. Model 2 is adjusted for age, sex, race, and vascular risk factors including body mass index (1 kg/m2 increment), smoking (current vs. non-current), estimated glomerular filtration rate (1 mL/min/1.73 m² increment), history of coronary artery disease, diabetes mellitus, hypercholesterolemia, hypertension, atrial fibrillation, and heart failure at baseline. Model 3 is additionally adjusted for circulating high-sensitivity C-reactive protein (hsCRP) levels. Analyses for 1 SD increment correspond to ln-transformed MCP-1 levels.