Gene-environment interactions shape cytokine-mediated inflammation and cardiovascular risk
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Supporting information
Accepted version
Author(s)
Type
Journal Article
Abstract
Background: Chronic inflammation is a major driver of cardiovascular diseases, but mechanisms linking
systemic inflammation to cardiac remodeling remain incompletely understood. We aimed to evaluate the role
of cytokine-mediated signaling and the influence of environmental and genetic factors on inflammation and
cardiac phenotypes in a large population-based cohort.
Methods: We analyzed subsets of 488,079 UK Biobank participants with metabolomic and proteomic profiling,
cardiac magnetic resonance (CMR) imaging, and longitudinal outcomes. Chronic inflammation was quantified using glycoprotein acetyls (GlycA) by nuclear magnetic resonance spectroscopy. Machine learning-based analysis extracted CMR phenotypes. Multivariable linear regression assessed GlycA-cardiac associations. Mediation analysis tested 80 inflammatory proteins as potential mediators. Cox models evaluated GlycA levels and major adverse cardiovascular events (MACE). An exposome-wide association study identified environmental determinants of inflammation, and gene-environment interactions were assessed using multi-ancestry polygenic risk scores.
Results: Higher GlycA levels were associated with reduced left ventricular indexed end-diastolic volume (β
=–2.09) and stroke volume (β =–1.12), with compensatory increased heart rate (β = 1.38; all P < 10−228).
Interleukin (IL)-1 receptor antagonist statistically mediated 27% of the GlycA effect on end-diastolic volume (average causal mediated effect–0.53 [95% CI,–0.64 to–0.41]; P < 10−16). The highest GlycA quintile had 43% higher MACE risk versus the lowest (adjusted HR, 1.43 [95% CI, 1.38–1.49]). Trunk fat mass (β = 0.35), current smoking (β =0.39), psychological distress, and low socioeconomic status were the strongest GlycA determinants (all P < 10−50). Cardiovascular polygenic risk scores modified associations between environmental exposures, inflammation, and MACE.
Conclusions: Chronic systemic inflammation is associated with reduced left ventricular volumes and increased cardiovascular risk in the community, with circulating cytokines and growth factors including IL-1 and TNF identified as potential mediators of these associations. Exposure-gene interactions are associated with inflammatory responses such that risk may reflect the convergence of inherited and acquired factors.
systemic inflammation to cardiac remodeling remain incompletely understood. We aimed to evaluate the role
of cytokine-mediated signaling and the influence of environmental and genetic factors on inflammation and
cardiac phenotypes in a large population-based cohort.
Methods: We analyzed subsets of 488,079 UK Biobank participants with metabolomic and proteomic profiling,
cardiac magnetic resonance (CMR) imaging, and longitudinal outcomes. Chronic inflammation was quantified using glycoprotein acetyls (GlycA) by nuclear magnetic resonance spectroscopy. Machine learning-based analysis extracted CMR phenotypes. Multivariable linear regression assessed GlycA-cardiac associations. Mediation analysis tested 80 inflammatory proteins as potential mediators. Cox models evaluated GlycA levels and major adverse cardiovascular events (MACE). An exposome-wide association study identified environmental determinants of inflammation, and gene-environment interactions were assessed using multi-ancestry polygenic risk scores.
Results: Higher GlycA levels were associated with reduced left ventricular indexed end-diastolic volume (β
=–2.09) and stroke volume (β =–1.12), with compensatory increased heart rate (β = 1.38; all P < 10−228).
Interleukin (IL)-1 receptor antagonist statistically mediated 27% of the GlycA effect on end-diastolic volume (average causal mediated effect–0.53 [95% CI,–0.64 to–0.41]; P < 10−16). The highest GlycA quintile had 43% higher MACE risk versus the lowest (adjusted HR, 1.43 [95% CI, 1.38–1.49]). Trunk fat mass (β = 0.35), current smoking (β =0.39), psychological distress, and low socioeconomic status were the strongest GlycA determinants (all P < 10−50). Cardiovascular polygenic risk scores modified associations between environmental exposures, inflammation, and MACE.
Conclusions: Chronic systemic inflammation is associated with reduced left ventricular volumes and increased cardiovascular risk in the community, with circulating cytokines and growth factors including IL-1 and TNF identified as potential mediators of these associations. Exposure-gene interactions are associated with inflammatory responses such that risk may reflect the convergence of inherited and acquired factors.
Date Acceptance
2026-08-18
Citation
European Journal of Preventive Cardiology (EJPC)
ISSN
2047-4873
Publisher
Oxford University Press
Journal / Book Title
European Journal of Preventive Cardiology (EJPC)
Copyright Statement
Copyright This paper is embargoed until publication. Once published the author’s accepted manuscript will be made available under a CC-BY License in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy).
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Publication Status
Accepted