Abstract WMP103: Proteome-wide Mendelian Randomization Screen Identifies Circulating Protein Mediators Of Early-onset Ischemic Stroke

Objective: Discover blood proteins mediating risk of early-onset ischemic stroke (IS) via Mendelian Randomization (MR) analyses. Background: About 10-15% of IS affect young adults (18-50 years) and, in contrast to declining rates in older individuals, IS incidence has risen in the young. Thus, new therapies tailored to early-onset IS are of urgent need. Design/Methods: We conducted a proteome-wide MR screen of 653 blood proteins for susceptibility to early-onset IS (18-65 years) and its subtypes (cardioembolic stroke, large artery atherosclerosis, small artery occlusion, other stroke, and undetermined strokes) using our previous framework ( Circulation , 2019). cis-pQTLs (LD r 2 <0.01; P<0.01) were derived from a meta-analysis of five pQTL GWAS (N≤20,509). Corresponding genetic effects on early and late-onset IS were derived from the Early-Onset Stroke Consortium (N case = 16,851; N control = 32,473) and Stroke Genetics Network (SiGN) GWAS (N case = 9,272; N control = 25,124), respectively. MR analyses were conducted using inverse variance weighted, weighted median, and MR-EGGER methods. Results: Previously reported biomarkers were found to mediate risk of early-onset IS including ABO (OR all stroke =1.10 per SD increase in genetically predicted levels; 95% CI, 1.05-1.15; P=2.8x10 -5 ) and MMP12 (OR all stroke =0.87; 95% CI, 0.82-0.93; P=2.1x10 -5 ). In addition, at Bonferroni significance, we identified two new mediators of early IS: vascular endothelial growth factor 2 (KDR ; OR small artery occlusion =1.94; 95% CI,1.6-2.4; P=2.1x10 -9 ) and urokinase-type plasminogen activator (PLAU; OR undetermined stroke =3.08; 95% CI,1.9-5.2; P=1.3x10 -5 ). Genetically predicted levels of these proteins were not significantly associated with late-onset IS (> 65 years), and MR effect estimates differed significantly between early vs. late-onset IS for KDR (I 2 =96; heterogeneity P=9.7x10 -7 ) and PLAU (I 2 =85; het. P=0.01). Conclusion: While targeting known protein mediators for IS at all ages may help reduce risk of early-onset IS, there are likely additional distinct etiological mechanisms precipitating premature IS that also may warrant specific therapeutic intervention. Study Supported By: NIH R01NS086905, R01NS100178, R01NS105150