Blood and adipose tissue DNA methylation in adults born preterm with a very low birth weight – a sibling comparison study

Preterm birth and very low birth weight (VLBW; &lt;1500 g) increase risks for poor health outcomes, potentially mediated by epigenetic modifications such as DNA methylation (DNAm). We hypothesized that DNAm differs between VLBW adults and their siblings in blood and adipose tissue. We studied 75 adults born preterm with VLBW and 73 same-sex sibling controls from the Adults Born Preterm Sibling Study. DNAm at cytosine–guanine dinucleotide (CpG) sites in blood and adipose tissue was assessed using Illumina EPIC 850K at a mean age of 29 years. Biological pathways were investigated with QIAGEN ingenuity pathway analysis (IPA). No differences were observed in blood DNAm. In adipose tissue, 458 CpG sites were differentially methylated (FDR <i>p</i> &lt; 0.05) between VLBW and siblings. Top sites were annotated to genes related to lipid metabolism (cg00264176 (<i>FADS2)</i>, 0.077 (0.007), FDR <i>p</i> = 3.24 × 10⁻¹⁴) and neural development (cg08277679 (<i>KIF26A)</i>, 0.053 (0.005), FDR <i>p</i> = 8.22 × 10⁻¹²). IPA identified enrichment for 81 pathways (FDR <i>p</i> &lt; 0.05). Our results suggest tissue-specific DNAm differences in VLBW adults compared to their siblings. The changes cluster in pathways related to lipid metabolism, neurodevelopment, and cardiometabolic regulation, suggesting lasting tissue-specific epigenetic modifications in VLBW adults. This study looked at how being born very early and very small (birth weight less than 1500 g) might affect long-term health through changes in genetic material DNA. We focused on a process called DNA methylation (DNAm). DNAm affects how actively genes work. We compared 75 adults born very small and premature to 73 of their siblings. We analyzed DNAm in blood and fat tissue when participants were 29 years old. No differences were found in blood samples. However, in fat tissue, we found 458 spots on the genetic material DNA that were activated differently in VLBW adults compared to their siblings. These changes were linked to genes involved in fat processing, heart health, and brain development. The findings suggest that being born early and very small cause lasting changes in how genes work in fat tissue. This could explain why adults who are born very small have higher risks for heart and metabolic diseases. These insights may help guide future treatments to improve health outcomes for people born premature or small.