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

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.

Authors

Institutions

Publication Details

Journal
Scientific Reports
Published
2026-09-29
DOI
https://doi.org/10.1038/s41598-026-69096-z
Primary Topic
Tryptophan and brain disorders
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

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

Meredith N. Braskie, Amrita K. Cheema, Robert A. Rissman, Ganesh Muneshwar Babulal et al.
Scientific Reports
Tryptophan and brain disorders
article

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

Meredith N. Braskie, Amrita K. Cheema, Robert A. Rissman, Ganesh Muneshwar Babulal, Raymond F. Palmer, Asma Hallab, Mónica Rivera Mindt, Matthew Borzage, Michael Donohue, Rocky Vig, Robert C. Barber, Stephanie Large, Yonggang Shi, Rajesh Ranjan Nandy, Kristine S. Yaffe, Raul Vintimilla, Sid E. O’Bryant, Rema Raman, David Mason, Beau M. Ances, Amy Kind, Zhengyang Zhou, Mark E. Mapstone, Carl V. Hill, Nicole Phillips, Melissa E. Petersen, Michelle M. Mielke, Badri Narayan Vardarajan, Jorge J. Llibre‐Guerra, Leigh Ann Johnson, Ozioma C. Okonkwo, Bradley T. Christian, James Richard Hall, Arthur W. Toga, Annie D. Cohen, Kevin King, Lisa Barnes, Roderick McColl, The Health and Aging Brain Study (HABS-HD) Study Team*, Joe Lee, Fan Zhang
article en

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.

Scientific ReportsVol. 16(1)
University of Southern California (US), Alzheimer's Association (US), Barrow Neurological Institute (US), University of Wisconsin–Madison (US), Fordham University (US), University of North Texas Health Science Center (US), The University of Texas at San Antonio Health Science Center (US), University of Pittsburgh (US), University of California, San Francisco (US), Georgetown University (US), University of California, Irvine (US), Washington University in St. Louis (US), Humboldt-Universität zu Berlin (DE), University Hospital Magdeburg (DE), Wake Forest University (US), Rush University (US), Columbia University (US), The University of Texas Southwestern Medical Center (US), Otto-von-Guericke-Universität Magdeburg (DE)
Good health and well-being
Openalex Percentile: Top 18%
Tryptophan and brain disorders
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.