Abstract
BACKGROUND: Subarachnoid hemorrhage (SAH) following aneurysmal rupture remains a devastating cerebrovascular event with limited predictive biomarkers. Accurate prediction of aneurysm rupture risk remains a clinical priority, as it could improve risk prediction and reveal potential therapeutic targets. Leveraging UK Biobank proteomic data, we aimed to identify protein markers associated with SAH risk using observational and genetic analyses.
METHODS: We analyzed data from 52 916 participants enrolled in the UK Biobank. The analysis involved 3 steps: (1) Longitudinal cox proportional hazards analyses between normalized circulating levels of 2923 proteins and incident nontraumatic SAH (aneurysmal or nonaneurysmal) adjusting for age, sex, ancestry, smoking status, hypertension, hyperlipidemia, and diabetes; (2) Proteins identified in step 1 (false discovery rate-adjusted P<0.05) underwent Mendelian randomization using cis-protein quantitative trait loci; (3) cellular expression profile of significant proteins were examined using single-cell transcriptomic from immunophenotypic atlas of human hematopoietic progenitors.
RESULTS: We identified 123 incident SAH cases; the mean follow-up was 7.06 years (SD, 3.53), the mean age was 59.28 (SD, 7.13), and 62% were females. SLAMF1 (signaling lymphocytic activation molecule family member 1) and NINJ1 (Ninjurin 1) were significantly associated (SLAMF1: HR per SD increase, 2.18 [95% CI, 1.49-3.18]; adjusted P<0.001; for NINJ1: HR, 1.85 [95% CI, 1.43-2.40]; adjusted P=0.004). Mendelian randomization confirmed the association for SLAMF1 (Inverse Variance Weighted approach OR, 1.73 [95% CI, 1.26-2.38]), with directionality supported through reverse Mendelian randomization (P>0.05). Single-cell transcriptomic analysis demonstrated high SLAMF1 expression in CD4-CTM, CD4-activated, and CD4-naive cells, indicating a possible immunologic role in SAH pathophysiology.
CONCLUSIONS: Our combined analytical approach identified SLAMF1 as a protein associated with increased SAH risk. SLAMF1, a receptor involved in modulating innate and adaptive immune responses, has been implicated in inflammatory and autoimmune diseases. SLAMF1 and related proteins represent promising biomarkers for SAH risk, potentially enhancing risk stratification, guiding preventive strategies, and informing future therapeutic development. Further research is necessary to explore its mechanistic role in SAH development.