Epigenetic factors have been suggested as mediators of early-life nutrition to future health. Prior studies focused on breastfeeding effects on DNA methylation (DNAm), ignoring other feeding modes. In this analysis of the Isle of Wight birth cohort, feeding modes were categorized as exclusive breastfeeding (EBF), exclusive formula feeding (EFF), and mixed feeding based on whether the respective feeding mode lasted for at least 3 months. In addition, in the past, infant feeding modes were assessed using DNAm at one time point in childhood, not changes of DNAm. In this paper, methylation differences (delta DNAm) were calculated by subtracting residual methylation values at birth from age 10 years (adjusting for cell types and season of blood collection at both ages). These deltas were estimated for all methylation sites where cytosine was followed by guanine (cytosine guanine dinucleotide (CpG) sites). Then, we performed an epigenome-wide association study contrasting EBF, EFF, and mixed feeding with delta DNAm that represents changes in methylation from birth to 10 years. A total of 87 CpGs (EBF: 27 CpGs, EFF: 48 CpGs, mixed: 12 CpGs) were identified using separate linear regression models adjusting for confounders and multiple testing. The sum of all changes in methylation from birth to age 10 years was significantly lower in the EFF group. Correspondingly, the number of CpGs with a methylation decline was 4.7% higher reflecting 13,683 CpGs. Lower methylation related to exclusive formula feeding and its adverse potential for the child’s development needs future research to reduce adverse health effects.

Patients with end-stage kidney disease (ESKD) display features of premature aging. There is strong evidence that changes in DNA methylation (DNAm) contribute to age-related pathologies; however, little is known about their association with premature aging and cardiovascular mortality in patients with ESKD. We assayed genome-wide DNAm in a pilot case-control study of 60 hemodialysis patients with (n=30, cases) and without (n=30, controls) a fatal cardiovascular event. DNAm was profiled on the Illumina EPIC BeadChip. Four established DNAm clocks (i.e., Horvath-, Hannum-, Pheno-, and GrimAge) were used to estimate epigenetic age (DNAmAge). Epigenetic age acceleration (EAA) was derived as the residuals of regressing DNAmAge on chronological age (chroAge), and its association with cardiovascular death was examined using multivariable conditional logistic regression. An epigenome-wide association study (EWAS) was performed to identify differentially methylated CpGs associated with cardiovascular death. All clocks performed well at predicting chroAge (correlation between DNAmAges and chroAge of r=0.76-0.89), with GrimAge showing the largest deviation from chroAge (a mean of +21.3 years). There was no significant association of EAAs with cardiovascular death. In the EWAS, a CpG (cg22305782) in the FBXL19 gene had the strongest association with cardiovascular death with significantly lower DNAm in cases vs. controls ( P FDR =2.0x10 −6 ). FBXL19 is involved in cell apoptosis, inflammation, and adipogenesis. Overall, we observed more accelerated aging in patients with ESKD, although there was no significant association of EAAs with cardiovascular death. EWAS suggests a potential novel DNAm biomarker for premature cardiovascular mortality in ESKD.