Protein epigenetic scores derived in neonatal saliva as biomarkers of childhood cognition.

Preterm birth is closely associated with immune dysregulation in early life and subsequent learning and psychiatric disorders, but methods for stratifying infants at risk remain elusive. Protein epigenetic Scores (EpiScores) are DNA methylation (DNAm)-based proxies of circulating proteins and can capture health-related exposures such as chronic inflammation. EpiScore of C-reactive protein (DNAm CRP) is associated with inflammatory burden in early life, atypical brain development following preterm birth and adult cognitive ability. To evaluate the utility of neonatal protein EpiScores for predicting childhood cognition, we examined associations of DNAm CRP and 42 other saliva-based EpiScores enriched for inflammatory proteins correlated with low gestational age, with cognition in a cohort of 231 children, including 154 preterm children assessed at 2 years and 127 preterm and term-born children assessed at 5 years. DNAm CRP was negatively associated with 5-year Mullen Scales of Early Learning Composite (ELC) (β = -0.273, p = 0.002). Association magnitudes were larger for children born earlier (DNAm CRP x gestational age, β