Genetically Determined Levels of Inflammation-Related Proteins and Functional Outcome After Ischemic Stroke: A Mendelian Randomization Study

Directionally concordant results were observed for three proteins in the secondary MR analysis: HGF (OR, 0.14 [0.06-0.37],FDR<0.001),CASP-8 (OR, 0.56 [0.33-0.94],P=0.028), and S100A12 (OR, 3.02 [1.32-6.90],FDR=0.045)(Figure 2B; details provided in Supplementary Tables 910111213).No significant or suggestive associations were observed for any of the remaining proteins.Our MR analyses indicate that S100A12 and MCP-3 exert a causal detrimental influence on ischemic stroke outcomes, aligning with clinical observations that elevated acute-phase levels are associated with poor outcomes. 2Importantly, MR reflects a lifelong genetic predisposition to constitutive protein exposure rather than transient post-injury responses.This distinction is Figure 1.Study design and workflow for MR analyzing the causal relation between inflammatory proteins (UK Biobank Pharma Proteomics Project) and func- tional outcome after ischemic stroke (GISCOME).Genetic instruments were filtered and adjusted for collider bias (GIGASTROKE).Four proteins were ineligible for downstream analysis (IL-6, STAMBP, 4E-BP1, and OSM because of having less than three SNPs and r <0.005).For the 10 remaining proteins, analyses were performed using both NIHSS-adjusted and unadjusted data, followed by comprehensive sensitivity analyses.