DNA methylation-based surrogate markers of C-reactive protein and their associations with health-related traits

Several methylation-based surrogate markers of C-reactive protein (mCRP) have been proposed and used to assess the risk of age-related phenotypes and construct novel ageing markers. We aimed to (i) assess the variance in plasma CRP explained by several mCRP markers; (ii) compare their associations with three health-related traits: mortality, body mass index (BMI), and PCGrimAge; and (iii) assess the stability of CRP and mCRP over a decade. Blood samples were collected from 947 participants in the Melbourne Collaborative Cohort Study at baseline (1990-1994) and wave 2 (2003-2007). High-sensitivity CRP was measured in plasma samples. Five mCRP markers were calculated: mCRP-Ligthart, mCRP-Wielscher, mCRP-EpiScore, mCRP-GrimAge2, and mCRP-Hillary. Intraclass correlation coefficients (ICCs) were calculated to assess the stability of CRP/mCRP between baseline and wave 2. Associations of wave 2 CRP/mCRP with mortality (N_deaths = 319) were assessed using Cox models and linear regression for BMI and age-adjusted PCGrimAge. mCRP explained 6.0% (mCRP-Wielscher) to 16.8% (mCRP-GrimAge2) of the variance in plasma CRP. The ICCs for CRP and mCRP markers were similar, ranging from 0.44 (mCRP-GrimAge2) to 0.63 (mCRP-Wielscher). Compared with CRP, mCRP had stronger associations with PCGrimAge, whereas for mortality and BMI, the associations were similar or weaker for mCRP. Associations between mCRP and mortality were greatly attenuated after adjusting for PCGrimAge but less so after adjusting for CRP. The association of CRP with mortality remained strong after adjusting for mCRP. Our study validated mCRP markers and clarified the role of CRP and mCRP in ageing, which may inform the use and development of ageing biomarkers.