Mediating effect of pro-inflammatory cytokines in the association between depression, anxiety, and cardiometabolic disorders in a multiethnic US population

Neuroinflammation is associated with depression and anxiety risk, both of which demonstrate a bilateral relationship with cardiometabolic disorders. Systemic inflammation was also commonly described in patients with cardiometabolic disorders. It is, thus, unclear whether pro-inflammatory cytokines might statistically mediate the relationship between depression, anxiety, and cardiometabolic disorders, particularly in advanced ages. 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 intermediate 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. In the 2,110 included cases, depression and/or anxiety were significantly associated with 58% higher odds of cardiovascular diseases (CVD) (OR = 1.58 [95% CI: 1.13–2.20]), 51% of type 2 diabetes (T2DM) (OR = 1.51 [95% CI: 1.22–1.87]), 22% of dyslipidemia (OR = 1.22 [95% CI: 1.01–1.49]), 28% of hypertension (OR = 1.28 [95% CI: 1.05–1.56]), and 40% of obesity (OR = 1.40 [95% CI: 1.17–1.68]). After adjusting for multiple covariates and multiple testing, only IL-6 showed a significant mediating role in the association of depression and/or anxiety with CVD (10%, p-value FDR = 0.030), T2DM (10%, p-value FDR = 0.027), hypertension (12%, p-value FDR = 0.027), and obesity (20%, p-value FDR = 0.027). The results remained statistically significant after additionally adjusting for the use of anti-inflammatory medication. Depression, anxiety, and higher odds of major cardiometabolic disorders were significantly associated, and IL-6 statistically mediated parts of these associations. As this study was based on self-disclosed diagnoses, future clinical studies are needed to replicate the findings and specifically cluster high-risk profiles. The cross-sectional design of the study presents a major limitation and no causal effects can be concluded from current results.