Genetically Determined Levels of Circulating Cytokines and Risk of Stroke

Abstract

Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether circulating levels of cytokines and growth factors are causally associated with stroke and its etiologic subtypes by conducting a two-sample Mendelian randomization (MR) study. 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 increased risk of

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Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

“…Also, there are few data on stroke and other cardiovascular outcomes beyond coronary artery disease. [9][10][11] Interleukin-6 (IL-6), a key regulator of the inflammatory cascade, acts by binding to either its membrane-bound or soluble receptor (IL-6R) and induces proinflammatory downstream effects including increases in the levels of C-reactive protein (CRP). 12,13 IL-6 has been implicated in the pathogenesis of multiple inflammatory diseases and inhibitors of IL-6R are used for the treatment of rheumatoid arthritis, 14 inflammatory bowel disease, 15 and other autoimmune disorders.…”

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer

“…Genome-wide association studies (GWAS), which have identified thousands of variants associated with complex traits, bring the wide usage of MR to a new climax 22,23 . Recently, a comprehensive MR analysis regarding genetically determined levels of circulating cytokines and risk of stroke gave us a good demonstration 24 . It was implemented leveraging the most comprehensive GWAS which evaluated 41 cytokines and growth factors in 8293 healthy subjects of Finnish ancestry 25 , and the largest GWAS meta-analysis on stroke and stroke subtypes to date (MEGASTROKE) 26 .…”