Mediating effect of pro-inflammatory cytokines in the association between depression, anxiety, and cardiometabolic disorders in a multiethnic US population
Abstract
Abstract 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.
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Authors: Asma Hallab, The Health and Aging Brain Study (HABS-HD) Study Team*, Sid E. O’Bryant, Kristine S. Yaffe, Arthur W. Toga, Robert A. Rissman, Leigh Ann Johnson, Meredith N. Braskie, Kevin King, James Richard Hall, Melissa E. Petersen, Raymond F. Palmer, Robert C. Barber, Yonggang Shi, Fan Zhang, Rajesh Ranjan Nandy, Roderick McColl, David Mason, Bradley T. Christian, Nicole Phillips, Stephanie Large, Joe Lee, Badri Narayan Vardarajan, Mónica Rivera Mindt, Amrita K. Cheema, Lisa Barnes, Mark E. Mapstone, Annie D. Cohen, Amy Kind, Ozioma C. Okonkwo, Raul Vintimilla, Zhengyang Zhou, Michael Donohue, Rema Raman, Matthew Borzage, Michelle M. Mielke, Beau M. Ances, Ganesh Muneshwar Babulal, Jorge J. Llibre‐Guerra, Carl V. Hill, Rocky Vig
Institutions: University of Pittsburgh, Georgetown University, Columbia University, University of California, San Francisco, Otto-von-Guericke-Universität Magdeburg, University of Southern California, Washington University in St. Louis, University of Wisconsin–Madison, The University of Texas at San Antonio Health Science Center, Humboldt-Universität zu Berlin, University of California, Irvine, The University of Texas Southwestern Medical Center, Wake Forest University, University Hospital Magdeburg, Fordham University, University of North Texas Health Science Center, Barrow Neurological Institute, Rush University, Alzheimer's Association