Abstract
We aimed to assess the role of traditional cardiovascular risk factors on carotid artery intima-media thickness (IMT) and proteins associated with IMT. IMT was measured in 50,704 participants from the UK Biobank. Plasma levels of 2923 proteins were analyzed in 6328 individuals. Mendelian randomization (MR) analyses used genetic data on IMT, proteins, and risk factors. Observational analyses showed positive associations of LDL-cholesterol, body mass index (BMI), diabetes, and systolic blood pressure (SBP) with IMT, while HDL-cholesterol was inversely related. MR analysis confirmed causality for LDL, BMI, diabetes, but not HDL. Of 63 proteins observationally linked to IMT, 17 were replicated externally. Five proteins (BCAM, NTproBNP/NPPB, RABEPK, ACAN, FN1) were associated with IMT in MR, with RABEPK showing concordant directional relationships. MR supports causal links between LDL, BMI, diabetes, SBP, and IMT. RABEPK emerged as a potential therapeutic target, warranting further investigation.