Childhood Adversity and Cardiovascular Disease Risk: Unraveling Plasma Proteomic Pathways and Moderating Role of Genetic Predisposition

BACKGROUND: Childhood adversity (CA) is associated with cardiovascular disease (CVD). Proteomic profiling may help elucidate underlying mechanisms. This study aimed to explore how CA and genetic risk jointly impact CVD and the potential role of proteomic biomarkers. METHODS: A total of 14 508 participants without baseline CVD and with available proteomics data from the UK Biobank were included. CA was assessed using the Childhood Trauma Screener questionnaire. Proteomic signatures were derived using least absolute shrinkage and selection operator regression. Cox proportional hazard models were used to examine the associations of CA with CVD, and mediation analyses were conducted to assess the extent to which proteomic biomarkers explained these associations. RESULTS: Over a median follow-up of 13.5 years, 2286 incident CVD events were identified. The per-score increase in CA score was associated with all-cause and cause-specific CVD, with hazard ratios (HRs) for all-cause CVD, coronary heart disease, arrhythmia/conduction disorder, and heart failure being 1.049 (95% CI, 1.031-1.068), 1.039 (95% CI, 1.009-1.070), 1.041 (95% CI, 1.015-1.067), and 1.066 (95% CI, 1.012-1.122), respectively. No significant interaction between CA and genetic risk was observed. Participants with both high CA and high genetic risk had the highest all-cause CVD risk (HR, 1.847 [95% CI, 1.380-2.472]). Several proteins (pro-adrenomedullin, agrin, AHNAK, CD302, CD83, and yes-associated protein 1) explained 1.58% to 9.98% of the associations between CA and all-cause and cause-specific CVD. Proteomic signatures statistically mediated 3.68% to 10.80% of these associations. CONCLUSIONS: CA and genetic susceptibility jointly contributed to increased CVD risk. Proteomic biomarkers partially mediate the CA-CVD associations, providing insight into biological pathways linking early-life adversity and CVD.