UCSF

Extremely premature infants exhibit substantial biological heterogeneity that contributes to differences in neonatal outcomes, including bronchopulmonary dysplasia (BPD), one of the most common complications among this population. However, the biological processes underlying this heterogeneity remain incompletely understood. While omics approaches provide powerful tools for investigating these processes, their application in extremely premature infants remains limited. This dissertation used metabolomic and genomic approaches to investigate the urinary metabolome of extremely premature infants at high risk of developing BPD by identifying metabolic dysregulation associated with BPD and determining how genetic variation captured by genomic ancestry proportions contributes to variation in metabolite levels. Metabolome-wide association analyses during the second and fourth weeks of life identified suggestive metabolite associations with BPD, leading to the enrichment of metabolic pathways involved primarily in amino acid and fatty acid metabolism. These patterns of metabolic dysregulation varied across time points and feeding modality (parenteral vs enteral nutrition), with most BPD-differential metabolites being at lower urinary levels during the fourth week of life in infants who develop BPD, particularly among those receiving parenteral nutrition. Beyond BPD-associated metabolic dysregulation, genomic analyses demonstrated that ancestry-linked genetic variation contributes to variation in the urinary metabolome of extremely premature infants. African genomic ancestry proportions were associated with histidine metabolites and enrichment of nucleotide metabolism pathway. Although limited overlap was observed between BPD-associated and ancestry-associated metabolic pathways, several metabolites showed nominal associations across both analyses, highlighting the potential contribution of ancestry-linked genetic variation to variability in clinically relevant metabolites. This dissertation demonstrates that the urinary metabolome of extremely premature infants is shaped by both BPD-associated metabolic dysregulation and ancestry-linked genetic variation, highlighting the value of integrating metabolomics and genomics to understand biological heterogeneity in this vulnerable population.