Plasma proteomic architecture of educational attainment associated with morbidity and mortality

Plasma Proteomic Architecture of Educational Attainment Associated with Morbidity and Mortality. This graphical abstract demonstrates that educational attainment is significantly associated with 599 proteins and 4 protein modules. Higher educational attainment was significantly positively correlated with protein module 0 [β = 2.7×10 -3 , 95%CI: 9.7×10 -4 to 4.5×10 -3 , P = 2.3×10 -3 ], module 1 [β = 9.0×10 -3 , 95%CI: 7.4×10 -3 to 1.1×10 -2 , P = 3.0×10 -27 ], and module 3 [β = 6.9×10 -3 , 95%CI: 5.3×10 -3 to 8.6×10 -3 , P = 1.3×10 -16 ], while significantly negatively correlated with module 8 [β = −1.7×10 -3 , 95%CI: −2.4×10 -3 to −1.0×10 -3 , P = 6.9×10 -7 ]. Higher educational attainment exerts a causal regulatory effect on the plasma proteome, mainly by downregulating key inflammatory proteins including IL-6, TNF, and CD4 [inverse variance weighted (IVW) Mendelian randomization analysis: for IL-6, β (95%CI): −0.22 (−0.29 to −0.15), P = 7.43×10 -10 ; for TNF, β (95%CI): −0.16 (−0.22 to −0.10), P = 2.99×10 -7 ; for CD4, β (95%CI): −0.18 (−0.26 to −0.11), P = 3.07×10 -7 ]. These inflammatory proteins further mediate the association between lower educational attainment and higher risk of morbidity and mortality, among which IL-6 explains 20.7% of the educational-mortality gradient. Higher educational attainment is robustly linked to lower morbidity and mortality, yet the underlying biological mechanisms remain elusive. To investigate how education shapes the plasma proteome and its role in health outcomes. We performed a proteome-wide association study (PWAS) and protein coexpression network analysis using plasma proteomic data from 43,282 participants in the UK Biobank. Linear regression identified educational attainment associated proteins. Protein-protein interaction (PPI) networks and functional enrichment were used to elucidate biological pathways. Mendelian randomization (MR) was used to test causal relationships between educational attainment and key proteins. Cox regression models were used to assess longitudinal associations of the identified proteins with health outcomes. Further causal mediation analysis quantified the mediating role of proteins in the education-health gradient. We identified 599 plasma proteins and 4 protein network modules significantly associated with education. These identified proteins were predominantly enriched in inflammation pathways. PPI network and hub analysis identified IL-6, TNF, and CD4 as central interactors. MR demonstrated a causal effect of higher educational attainment on lower levels of key inflammatory proteins (IL-6, TNF, and CD4; IVW P < 2.99 × 10 -7 ). These MR-PPI-identified proteins were significantly associated with health outcomes. Causal mediation analysis further established these key proteins, especially IL-6, as significant mediators explaining the gradient effect of education on health. This study provides robust evidence that educational attainment substantially shapes the plasma proteome, with inflammatory disturbance serving as a major biological conduit to adverse health outcomes. Through the identification of specific causal proteins and quantification of their mediating effects, we reveal potential targets to counteract the adverse health consequences associated with lower educational attainment. This work brings us closer to understanding, and potentially interrupting, the biological mechanisms that drive education-related health disparities.