Abstract Number: Esoc2026a2044 Context-Dependent PQTLS Reveal Blood Pressure–specific Molecular Mechanisms Linked to Vascular Brain Diseases

Abstract Background and aims Genetic regulation of circulating proteins, captured by protein quantitative trait loci (pQTLs), provides insight into molecular mechanisms underlying common diseases. However, most pQTL studies overlook the pathological context in which genetic effects operate, limiting our understanding of context-dependent causal mechanisms. We aimed to characterize the blood pressure–dependent genetic architecture of circulating proteins and its implications for the pathophysiology of vascular brain diseases. Methods We analyzed 2,923 plasma proteins quantified using Olink HT and 9,085,943 genetic variants in 32,399 UK Biobank participants. Individuals were classified into three strata based on repeated blood pressure measurements: normotensive, persistent hypertensive, and variable hypertensive. Genome-wide pQTL mapping was performed using linear regression, followed by heterogeneity testing and colocalization analyses to identify blood pressure–dependent pQTL effects. Mendelian randomization and colocalization analyses were conducted to investigate the relationship between significant pQTLs and cerebrovascular traits. Results We identified significant pQTLs for 1,751 proteins across blood pressure strata. pQTLs were detected for 1,561 proteins in persistent hypertensives, 1,713 in variable hypertensives, and 1,477 in normotensives. Several proteins, including XRCC4, EPCAM, GMFG, APP, PRCP, and RAB44, showed marked heterogeneity across blood pressure groups. Notably, APP has been linked to dementia and cerebral amyloid angiopathy, PRCP to cardiovascular regulation, and GMFG and XRCC4 to inflammatory and vascular processes implicated in stroke risk. Conclusions Our findings demonstrate that genetic effects on circulating protein levels vary by blood pressure–related pathological context. Proteins influenced by blood pressure–dependent genetic effects are established candidates for vascular brain diseases. Replication and functional validation studies are ongoing. Conflict of interest Jara Cárcel-Márquez: nothing to disclose; Stephanie Debette: nothing to disclose; Israel Fernández-Cadenas: nothing to disclose; Aniket Mishra: nothing to disclose.