DNA methylation-derived CRP captures chronic inflammatory pathways from metabolic risk to impaired lung function: a community-based prospective cohort study

Lung function decline predicts respiratory and age-related adverse health outcomes and may be influenced by metabolic dysfunction through systemic inflammation. DNA methylation-derived biomarkers can capture molecular signatures of chronic biological processes and may provide complementary information beyond circulating inflammatory markers. We investigated whether inflammatory markers mediate this association, comparing high-sensitivity C-reactive protein (hs-CRP) with DNA methylation–derived CRP score (DNAm-CRP). We analyzed 664 participants from the Korean Genome and Epidemiology Study. Metabolic component count (0–5), based on abdominal obesity, blood pressure, fasting glucose, triglycerides, and HDL-C were assessed across 2001–2010. hs-CRP and DNAm-CRP (from 1,465 CRP-associated CpG sites) were measured during 2009–2010, and lung function (FVC [mL], FEV 1 [mL], FEV 1 /FVC [%]) was assessed during 2009–2010 and 2013–2014. Multivariable linear regression estimated associations of metabolic component count with hs-CRP, DNAm-CRP, and lung function. Mediation analyses quantified indirect effects, and LASSO regression identified CpG sites jointly associated with chronic inflammation and lung function. Each 1-point increase in metabolic component count was associated with lower FVC (β: − 68.0, P < 0.001) and FEV 1 (β: − 35.7, P < 0.05) at 8-year follow-up. For lung function measured in 2009–2010, DNAm-CRP mediated a larger proportion of the metabolic risk–lung function association than hs-CRP (FVC: 14.1% vs. 7.7%; FEV 1 : 19.6% vs. 9.7%; all P < 0.05). After FDR correction, 29 and 37 CpGs remained associated with FVC and FEV₁, respectively, of which 36 CpGs mapped to gene regions, including 14 located promoter regions (e.g., cg05603985 in SKI ). Metabolic risk is associated with subsequent lung function through inflammatory pathways. DNAm-CRP captured a greater proportion of this effect than circulating hs-CRP, suggesting its potential as a robust marker of chronic inflammation.