Gene-exposure interactions regulate cytokine-mediated chronic inflammation and cardiac remodeling

Background Chronic inflammation predicts adverse cardiovascular outcomes, but mechanisms linking systemic inflammation to cardiac remodeling remain incompletely understood. Purpose We investigated associations between circulating inflammatory biomarkers and cardiac phenotypes in a population-based cohort and examined how environmental exposures and genetic susceptibility influence inflammatory responses. 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 restrictive cardiac remodeling: 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 mediated 27% of the GlycA effect on end-diastolic volume (average causal mediated effect –0.51 [95% CI, –0.53 to –0.64]; 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. Conclusion Chronic systemic inflammation is associated with restrictive cardiac remodeling and increased cardiovascular risk mediated by circulating cytokines and growth factors. Individual inflammatory responses are shaped by gene-environment interactions, highlighting the complex interplay between genetic susceptibility, environmental exposures, and their cumulative impact on cardiovascular health. This is especially relevant given the increasing number of clinical trials evaluating therapies that modulate inflammation across cardiovascular and non-cardiovascular conditions.