Abstract
PURPOSE: To evaluate the associations of hypertension history, blood pressure (BP) levels, and parameters with retinal vascular occlusion (RVAO) risk, and to identify potential mediating plasma proteins. METHODS: The cohort study used data from 439,057 UK Biobank participants. Multivariable Cox regression was used to evaluate associations between incident RVAO and exposures: hypertension history (with stratification of control status and disease duration), hypertension stages (per 2017 guidelines), systolic BP (SBP), diastolic BP (DBP), mean arterial BP (MABP), and pulse pressure (PP). Mendelian randomization (MR) was subsequently used to assess causality and identify mediating plasma proteins. RESULTS: In observational analysis, hypertension history (uncontrolled and long/unknow duration), stage 1 hypertension, stage 2 hypertension, higher BP parameters (SBP, MABP, and PP) were associated with an increased risk of RVAO, whereas DBP showed no significant association. The MR analysis supported the causal relationships for hypertension history and SBP but not for DBP. Six plasma proteins were identified as potential mediators for the hypertension history, with secretory leukocyte peptidase inhibitor (SLPI) explaining the largest proportion of the effect (13.3%). Ankyrin Repeat and SOCS Box Containing 9 (ASB9) was found to mediate the effects for both hypertension history (3.56%) and SBP (4.31%) to RVAO. CONCLUSIONS: Hypertension history and elevated SBP were significant risk factors for RVAO. Specific plasma proteins, notably SLPI and ASB9, may serve as mediators and represent potential targets for therapeutic intervention. TRANSLATIONAL RELEVANCE: The identification of mediating plasma proteins, such as SLPI and ASB9, provides novel therapeutic targets and biomarkers for preventing RVAO among individuals with hypertension.