PLASMA PROTEIN LEVEL RATIOS IDENTIFY NOVEL CIRCULATING TARGETS ASSOCIATED WITH STROKE RISK

Previous studies have nominated individual plasma proteins as therapeutic targets for stroke. Whether ratios of protein levels, which can capture relative pathway activity, are causally related to stroke remains unknown. We evaluated the potential causal associations between plasma protein level ratios and stroke risk. We conducted bidirectional, two-sample Mendelian randomization (MR) to estimate the associations between circulating protein level ratios and overall stroke and stroke subtypes. Pathway enrichment and protein–protein interaction (PPI) analyses were used to explore potential mechanisms. Forward MR indicated that a higher TGFBR2/THBD ratio was associated with increased risk of any ischemic stroke (AIS) (OR = 1.15; 95% CI, 1.09–1.21; p = 4.07e-7). A higher GP1BA/SDC4 ratio was associated with increased risk of small-vessel stroke (SVS) (OR = 1.25; 95% CI, 1.14–1.37; p = 2.25e-6), whereas a higher SDC4/SEMA4D ratio was associated with lower SVS risk (OR = 0.82; 95% CI, 0.76–0.89; p = 1.18e-6). Reverse MR found no evidence that AIS or SVS causally influenced these ratios, supporting the inferred direction of effect. Sensitivity analyses supported the robustness of the estimates. Pathway enrichment and PPI analyses implicated TGF-β signaling and coagulation in AIS pathobiology, and platelet activation, extracellular matrix organization, and axon guidance in SVS. Plasma protein level ratios may help identify biologically relevant pathways and therapeutic targets for stroke prevention and treatment.