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

Abstract

AbstractChronic 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 18% of phenotypic variance in the LBC1936 cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (ALSPAC, HELIOS, SABRE, LBC1921), including individuals of diverse genetic ancestry and from different age groups. The newly-described predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.