Early-Life DNA methylation at TRIM6 and TTC23 promoters associates with respiratory infections at one year

BACKGROUND: DNA methylation (DNAm) is a well-characterized epigenetic modification that serves as a predictive marker of disease risk across the lifespan. Given the rapid development of the first 1000 days, infancy represents a critical window for examining how pediatric epigenetic signatures may shape future health trajectories. METHODS: Here, we examined associations between blood DNAm in 3-month-old infants from a Canadian birth cohort and the number of respiratory infections experienced between 12 and 18 months of age, hypothesizing that a potential epigenetic signature in early-life might be predictive of future risk. RESULTS: We discovered eight CpG sites with increased DNAm in the promoter regions of two genes: TRIM6 and TTC23. Post hoc characterization suggested that the CpGs in TRIM6 might have functional relevance in CD4T cells. Further, both genes are involved with immune system regulation and respiratory function, processes directly relevant to the investigated health outcome: respiratory infections. Additionally, the associated CpGs in TRIM6 were replicated in a second Canadian birth cohort with similar characteristics, propensity-matched on number of respiratory infections and estimated cell type proportions. CONCLUSION: Together these findings illuminated the potential utility of DNAm as a predictor of future respiratory infections in pediatric populations. IMPACT: DNAm signatures in infancy may help predict later susceptibility to respiratory infections, highlighting early-life epigenetic marks as potential risk indicators. Our study identified differentially methylated CpGs within the promoter regions of only two genes, TRIM6 and TTC23, an uncommon pattern that may point to biologically meaningful regulation. These findings expand on existing EWAS literature by showing that persistent, biologically relevant DNAm differences can be detected across cohorts, underscoring their predictive potential for lifelong health outcomes.