METHODS: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study (GWAS) of 8,293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE GWAS dataset (67,162 cases; 454,450 controls) applying inverse-variance-weighted meta-analysis, weighted-median analysis, MR-Egger regression, and multivariable MR. The UK Biobank cohort was used as an independent validation sample (4,985 cases; 364,434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits using publicly available GWAS data.
RESULTS: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (OR per 1-SD increase: 1.06, 95% CI: 1.02-1.09, p=0.0009), any ischemic stroke (OR: 1.06, 95% CI: 1.02-1.10, p=0.002), large artery stroke (OR: 1.19, 95% CI: 1.09-1.30, p=0.0002) and cardioembolic stroke (OR: 1.14, 95% CI: 1.06-1.23, p=0.0004), but not with small vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR: 1.08, 95% CI: 0.99-1.17, p=0.09; any ischemic stroke: OR: 1.07, 95% CI: 0.97-1.18, p=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR: 1.04, 95% CI: 1.00-1.08, p=0.04) and myocardial infarction (OR: 1.05, 95% CI: 1.01-1.09, p=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in stroke patients compared to controls.
CONCLUSIONS: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, particularly with large artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.
- Centre for Clinical Brain Sciences - Chair of Neurology and Clinical Epidemiology
- Edinburgh Neuroscience
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Neurology and Clinical Epidemiology
- Usher Institute
- Centre for Medical Informatics
- Cerebrovascular Research Group
Person: Academic: Research Active