Plasma proteins associated with psychosocial factors and cardiovascular disease: The Jackson Heart Study

Authors: O'BRIEN, SARA - University Of North Carolina; GILLMAN, MADELINE - University Of North Carolina; GREEN, MICHAEL - Duke University School Of Medicine; CRUZ, DANIEL - Beth Israel Deaconess Medical Center; FLOYD, JAMES - University Of Washington; HANKINSON, SUSAN - University Of Massachusetts, Amherst; KATZ, DANIEL - Stanford University School Of Medicine; LIU, XIAOJUAN - Brigham & Women'S Hospital; ODDEN, MICHELLE - Stanford University School Of Medicine; PSATY, BRUCE - University Of Washington; REINER, ALEXANDER - University Of Washington; ROTTER, JEROME - Harbor-Ucla Medical Center; RICH, STEPHEN - University Of Virginia School Of Medicine; GERTSZTEN, ROBERT - Beth Israel Deaconess Medical Center; SHAH, AMIL - University Of Texas Southwestern Medical Center; SIMS, MARIO - University Of California, Riverside; TAHIR, USMAN - Beth Israel Deaconess Medical Center; TINKER, LESLEY - Fred Hutchinson Cancer Research Center; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); YU, BING - University Of Texas Health Science Center; ZANNAS, ANTHONY - University Of North Carolina; RAFFIELD, LAURA - University Of North Carolina; GLOVER, LASHAUNTA - Duke University School Of Medicine

Submitted to: Arteriosclerosis Thrombosis and Vascular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/6/2026
Publication Date: 3/26/2026
Citation: O'Brien, S.N., Gillman, M.G., Green, M.D., Cruz, D.E., Floyd, J.S., Hankinson, S., Katz, D.H., Liu, X., Odden, M.C., Psaty, B.M., Reiner, A.P., Rotter, J.I., Rich, S.S., Gertszten, R.E., Shah, A., Sims, M., Tahir, U.A., Tinker, L.F., Wood, A.C., Yu, B., Zannas, A.S., Raffield, L., Glover, L. 2026. Plasma proteins associated with psychosocial factors and cardiovascular disease: The Jackson Heart Study. Arteriosclerosis Thrombosis and Vascular Biology. 46:Article e324125. https://doi.org/10.1161/ATVBAHA.125.324125.
DOI: https://doi.org/10.1161/ATVBAHA.125.324125

Interpretive Summary: Cardiovascular disease remains one of the leading causes of death in the United States, and African American adults are disproportionately affected. Psychological stress and depressive symptoms are known to increase heart disease risk, This study identified several proteins in the blood linked to depressive symptoms in adult African-Americans, including Angiopoietin-2 and GDF-15 (also called MIC-1), which are involved in inflammation and vascular health. Importantly, GDF-15 partially explained the link between depressive symptoms and future coronary heart disease, accounting for about 23% of the association. These findings suggest that psychosocial stress may influence heart disease risk in part through measurable biological changes in circulating proteins. Understanding these pathways could help clinicians and researchers identify individuals at higher cardiovascular risk based on psychosocial profiles and may guide future prevention strategies. For scientists and policymakers, this work highlights the importance of integrating mental health and cardiovascular prevention efforts, particularly in populations experiencing higher disease burden.

Technical Abstract: Knowledge of proteomic mechanisms explaining the link between psychosocial stress and cardiovascular disease is limited. This study aimed to (1) identify plasma proteins associated with psychosocial factors and (2) assess associational pathways between psychosocial factors, identified proteins, and incident cardiovascular disease events in a discovery cohort, JHS (Jackson Heart Study), and 2 replication cohorts, the CHS (Cardiovascular Health Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). JHS participants from exam 1 (2000-2004) with SomaScan 1.3k platform proteomics data were included (n=2143, mean age=55.3). Depressive symptoms and perceived stress scores were measured via the 20-item Centers for Epidemiological Studies scale and an 8-item perceived stress scale adapted for the JHS, respectively. Multivariable linear regression models were used to test the association between psychosocial factors and plasma proteins, controlling for age, sex, proteomics batch, and estimated glomerular function. Meta-analyses were also performed across cohorts, using Bonferroni correction for multiple testing (P<3.782×10**-5). Mediation analyses with Cox proportional hazards models were used to evaluate potential proteomic pathways in the association between psychosocial factors and coronary heart disease, heart failure, and stroke in JHS. Angiopoietin-2 (Beta=0.013, SE=0.002, P<0.001), contactin-5 (Beta =-0.013, SE=0.002, P<0.001), growth/differentiation factor 15 or macrophage inhibitory cytokine 1 (Beta=0.011, SE=0.002, P<0.001), neural cell adhesion molecule 120 (Beta=-0.012, SE=0.002, P<0.001), and KYNU (kynureninase; Beta=0.014, SE=0.003, P<0.001) were each significantly associated with depressive symptoms, with angiopoietin-2, contactin-5, macrophage inhibitory cytokine 1, and neural cell adhesion molecule 120 replicating in CHS and MESA. Leukotriene A-4 hydrolase was associated with perceived stress (Beta=-0.0235, SE=0.005, P<0.001). Macrophage inhibitory cytokine 1 partially accounted for the association between depressive symptoms and incident coronary heart disease in JHS (23%; P=0.0009). Novel associations between psychosocial factors, plasma proteins, and cardiovascular disease were identified in JHS. Circulating proteomic profiles across 3 cardiovascular disease cohorts showed differences in protein concentrations by psychosocial measures. Future investigations should identify additional potentially targetable proteomic mechanisms by which psychosocial factors contribute to disease.