The association of placental gene expression and newborn metabolic profiles in understanding childhood asthma pathogenesis

Interactions between the genome and environment can be assessed through examination of metabolic profiles. As the development of asthma is highly influenced by genetic and environmental factors, assessment of meta- bolic profiles can improve our understanding of disease pathogenesis. We have demonstrated that select me- tabolite concentrations at birth are associated with risk of early life wheezing and asthma. Further, we have identified genetic pathways linking birth metabolic profiles with childhood asthma. While these findings shed some light on biologic processes leading to asthma development, we do not understand intermediary pro- cesses, such as gene expression within specific tissues, that may identify and allow targeting of disease-caus- ing pathways. Placental changes have been shown to be associated with certain diseases in childhood. How- ever, very little is known about the impact of placental changes in the development of childhood asthma. Given the immunomodulatory and metabolic role of the placenta and its importance in mitigating adverse effects from the environment, this organ is likely to play an important role in asthma susceptibility and resilience. The overall objective of this proposal is to elucidate placental-specific transcriptomic pathways impacting the metabolome and underlying childhood asthma pathogenesis. The rationale is that identifying relationships be- tween placental-specific transcriptomic pathways, newborn metabolism, and childhood asthma will expand our understanding of the fetal programming of asthma, highlight an asthma-relevant tissue, and identify target genes for prioritization of future functional characterization. We will pursue the following specific aims: 1) deter- mine associations between predicted gene expression in human placenta and early life wheezing and asthma- related newborn metabolite concentrations, and 2) determine associations between placental predicted expres- sion and early life wheezing and asthma and estimate the effect of placental predicted expression on childhood asthma that is mediated through newborn metabolite concentrations. To achieve Aim 1, we will generate pla- cental gene expression data from an ongoing pregnancy cohort and regress predicted expression on metabo- lite concentrations using genotypes and targeted newborn metabolites from a prospective birth cohort. To achieve Aim 2, we will utilize placental expression data outlined in Aim 1 and wheezing and asthma summary statistics from large GWAS to determine associations between placental predicted gene expression and wheezing and asthma. We will then perform a mediation analysis using findings from our previous work and findings from Aims 1 and 2A to estimate the fraction of the effect of placental gene expression on childhood asthma that is mediated by newborn metabolite concentrations. Potential impact: Successful completion of the proposed research will provide important insights on the role of the placenta in the development of childhood asthma and identify potential targets for prevention. As asthma is among the most prevalent chronic diseases of childhood, development of effective prevention strategies could have enormous public health impact. Project Number: 5R03HL177130-02 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Brittney Snyder | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $131,965 | Activity Code: R03 | Study Section: ZHL1-CSR-Q(O1) View on NIH RePORTER: https://reporter.nih.gov/project-details/5R03HL17713002