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<p>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, <i>p</i> = 0.002). Association magnitudes were larger for children born earlier (DNAm CRP x gestational age, β<sub>interaction</sub> = 0.181). DNAm&#xa0;CD209 was positively associated with 5-year ELC (β = 0.267, adjusted <i>p</i> &lt; 0.005). Fourteen other EpiScores were nominally associated with either 2-year Bayley-III Cognitive composite or 5-year ELC (absolute β range 0.180 to 0.245, <i>p</i> &lt; 0.05). For preterm children, associations of DNAm CCL18 with 2-year cognition (β = 0.182, <i>p</i> = 0.039) and of DNAm CRP (β = −0.318, <i>p</i> = 0.021) and DNAm CRTAM (β = −0.307, <i>p</i> = 0.008) with 5-year cognition remained significant after adjustment for inflammatory exposures. We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月24日

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  • Rebekah Smikle,
  • Katie Mckinnon,
  • Kadi Vaher,
  • Helen Turner,
  • Hilary Cruickshank,
  • Ray Amir,
  • Yu Wei Chua,
  • Eleanor L. S. Conole,
  • Rebecca M. Reynolds,
  • G. David Batty,
  • Athanasios Tsanas,
  • Lee Murphy,
  • Heather C. Whalley,
  • Riccardo E. Marioni,
  • Simon R. Cox,
  • James P. Boardman

摘要

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, βinteraction = 0.181). DNAm CD209 was positively associated with 5-year ELC (β = 0.267, adjusted p < 0.005). Fourteen other EpiScores were nominally associated with either 2-year Bayley-III Cognitive composite or 5-year ELC (absolute β range 0.180 to 0.245, p < 0.05). For preterm children, associations of DNAm CCL18 with 2-year cognition (β = 0.182, p = 0.039) and of DNAm CRP (β = −0.318, p = 0.021) and DNAm CRTAM (β = −0.307, p = 0.008) with 5-year cognition remained significant after adjustment for inflammatory exposures. We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.