Abstract Body: Background: Stroke remains one of the leading causes of death and morbidity worldwide, with a disproportionately higher burden among women. Recent advancements in omics, including proteomics, present a unique opportunity to uncover sex differences in pathways implicated in stroke.
Methods: Using the OLINK platform, 2,911 proteins were measured in 24,041 men and 28,251 women from the UK Biobank, including 609 men and 445 women who developed ischemic stroke (IS). Median time from blood collection to IS was 8.6 years (IQR 5.0–11.3) in men and 9.1 years (IQR 5.5–12.0) in women. Each IS case was matched to 20 age-matched controls. Sex-specific associations between proteins and IS were assessed using conditional logistic regression (CLR) adjusted for demographic, clinical, and behavioral factors. Proteins significantly associated with IS (FDR p-value < 0.05) in at least one sex were used to derive sex-specific IS scores via LASSO logistic regression (70% training, 30% testing). Sex differences in protein–IS associations were evaluated using protein–sex interaction terms in CLR models that were fit to a combined sample of men and women.
Results: 148 proteins were associated with incident IS in men (29 proteins), women (92 proteins), or both (27 proteins), meeting an FDR p-value < 0.05. No protein showed a significant protein-sex interaction at FDR p-value < 0.05. However, 9 proteins showed suggestive sex interactions (p-value < 0.05; FDR p-value < 0.12). These proteins were involved in immune regulation, posttranslational modification, cell adhesion and signaling, and synaptic function. Cerebellin-4 was inversely associated with IS in women (odds ratio (OR) = 0.84, 95% CI: 0.77–0.93) but not in men (OR = 0.99, 95% CI: 0.91–1.07). Ribonuclease T2 and Desmocollin-2 were each positively associated with IS in both sexes, with stronger effects in women, while the remaining six proteins were significantly positively associated with IS in women only. The sex-specific IS scores remained significantly associated with IS after adjusting for risk factors, with ORs per 1 SD increase of 1.42 (95% CI: 1.18–1.70) in men and 1.58 (95% CI: 1.30–1.93) in women.
Conclusion: This study identifies proteomic signatures associated with incident IS risk in men and women. Proteins having sex-specific associations were primarily involved in pathways related to immune response, intercellular signaling, post-translational modification, and synaptic function and plasticity.