Blood-based epigenome-wide analysis of chronic low-grade inflammation across diverse population cohorts

Chronic inflammation is a hallmark of ageing and age-related disease states. The effectiveness of inflammatory proteins such as C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N=17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic net regression-based predictor outperformed competing methods and explained 17% of phenotypic variance in the Lothian Birth Cohort 1936, doubling that of existing DNAm predictors. DNAm predictors performed comparably in three additional test cohorts, including individuals of European and South Asian ancestries and from childhood to later-life. The newly-described predictor surpassed assay-measured CRP and a genetic risk score in its associations with 28 health outcomes. Our findings forge new avenues for assessing chronic inflammation in diverse populations.