Mediating effect of pro-inflammatory cytokines in the association between depression, anxiety, and cardiometabolic disorders in an ethnically diverse community-dwelling middle-aged and older US population

Introduction Neuroinflammation is associated with depression and anxiety risk, both of which demonstrate a bilateral relationship with cardiometabolic disorders. Systemic inflammation is also commonly described in patients with cardiometabolic disorders. It is, thus, unclear whether pro-inflammatory cytokines might mediate the relationship between depression, anxiety, and cardiometabolic disorders, particularly in advanced ages. Methods The multiethnic ≥ 50-year-old study population is a subset of the Health and Aging Brain Study: Health Disparities (HABS-HD). Adjusted logistic and linear regression models were applied to assess associations. Non-linearity was evaluated using restricted cubic splines. Statistical mediation analysis was used to determine the role of inflammation (Tumor Necrosis Factor-alpha (TNF-alpha) and Interleukin-6 (IL-6)). Models were corrected for multiple testing using the False Discovery Rate (FDR)-method. Results In the 2,093 included cases, depression and/or anxiety were significantly associated with 62% higher odds of Cardiovascular Disorder (CVD) (OR=1.62 [95% CI: 1.22-2.15]), 54% of type 2 diabetes (T2DM) (OR=1.54 [95% CI: 1.29-1.85]), 26% of hypertension (OR=26% [95% CI: 1.07-1.48]), and 29% of obesity (OR=1.29 [95% CI: 1.11-1.51]). Only IL-6 showed a significant mediating role in the association of depression and/or anxiety with CVD (10%, p-value FDR =0.016), T2DM (13%, p-value FDR <0.001), hypertension (16%, p-value FDR <0.001), and obesity (23%, p-value FDR <0.001). Conclusions Depression and anxiety were significantly associated with higher odds of major cardiometabolic disorders, and IL-6 partly mediated these associations. Clinical studies are needed to replicate the findings and specifically cluster high-risk profiles.