A multidimensional proteomic framework of circulating inflammation identifies outcome-specific cardiovascular risk axes in 39,494 UK biobank participants

Abstract Inflammation is central to cardiovascular disease, yet conventional biomarkers do not resolve the underlying organisation of circulating inflammatory biology. Among 44,787 UK Biobank participants passing proteomic quality control, 736 inflammation-related proteins were used to derive orthogonal proteomic dimensions in a White Development sample (n = 20,830), with definitions fixed and applied unchanged in White Validation (n = 20,831). A CVD-free multimodal cohort of 39,494 participants provided the source population for downstream analyses; primary prospective associations were evaluated in White Development complete cases (n = 17,334) and replicated in White Validation (n = 17,190). Eight dimensions showed high structural stability and distinct protein, pathway, metabolic, imaging, and cardiovascular profiles. In the primary analysis, 23 of 48 RC outcome associations were FDR significant; RC2 was positively associated with all six outcomes, with the strongest association for heart failure (HR 1.395, 95% CI 1.273–1.527), while RC8 showed a more moderate but similarly broad pattern. RC4 was mainly associated with coronary outcomes, RC6 showed inverse associations with several endpoints, and RC7 was most clearly related to heart failure and atrial fibrillation. Major patterns reproduced in White Validation. Adding RC1–RC8 improved discrimination across all six outcomes (ΔC-index 0.0055–0.0136), with incremental gains retained beyond CRP, GlycA, and NLR. These findings support a reproducible multidimensional proteomic architecture of inflammation with heterogeneous cardiovascular relevance.