Plasma proteomic signatures of social support and their association with cardiovascular disease and mortality.

Background: Social support has been related to cardiovascular disease (CVD) incidence and mortality in longitudinal cohort analyses, but the biological pathways underpinning this remain underexplored. We explored the protein signatures of social support amongst older adults and the mediating effect of proteins in the association between social support and CVD and mortality. Methods: Data from 3,141 adults over the age of 50 in the English Longitudinal Study of Ageing who had plasma proteome data were analysed, with CVD and mortality outcomes followed up for 16 years following through Hospital Episode Statistics and the National Health Service Central Registry. Linear and Cox regression analyses were used to identify proteins associated with social support, CVD and mortality. Mediation analysis was then performed on the identified proteins to examine their role as a potential mediator between social support and CVD and mortality risk. Results: Over a median of 15.8-year follow-up, 889 participants have died, and 627 developed CVD. Of 276 proteins measured, greater social support was associated with lower levels of 13 proteins (EFNA4, SKR3, TNFRSF10A, TNFRSF11A, TRAIL-R2, Gal-9, FGF-23, REN, VSIG2, AMBP, MMP12, ASGR1, PSG1) and higher TN-R levels, after adjusting for baseline socioeconomic confounders. Of these 13 proteins, six proteins (TNFRSF10A, TNFRSF11A, FGF-23, VSIG2, AMBP, and ASGR1) were significantly associated after full adjustments. We also identified 49 protein-CVD and 70 protein-mortality associations after minimal adjustments, including 11 and 14 proteins simultaneously associated with social support. In the mediation analysis, each protein showed significant indirect effects: all the significant proteins together mediated about 20.9% and 26.4 % of the associations for CVD and mortality, respectively. The main enriched biological pathways involved death receptor activity and carbohydrate binding. Conclusions: Social support was related to proteomic signatures and these proteins mediated the association between social support and CVD and mortality risk, independently and cumulatively. These findings deepen our understanding of the intricate connections between relationship quality, proteins, and CVD and mortality development.