Asthma is the most common chronic disease among children globally. Disruptions of fetal development processes are
hypothesized to give rise to asthma, therefore, prenatal interventions may help reduce its short- and long-term burden.
Randomized clinical trials, including our Vitamin D Antenatal Asthma Reduction Trial (VDAART), have suggested that
maternal vitamin D supplementation can help prevent asthma in the offspring. However, in these trials, not all children
benefited from maternal vitamin D supplementation, and not all treated mothers had sufficient vitamin D levels. This
variability in vitamin D response suggests complex mechanisms underlying the potential protective effect of maternal
vitamin D on childhood asthma that are currently not well-understood. Our long-term goal is to uncover the molecular
mechanisms that can enable the precision prevention of childhood asthma. The objective of this application is to
identify the multi-omic determinants that modulate the influence of maternal vitamin D supplementation on childhood
asthma outcomes. Our central hypothesis is that the effect of maternal vitamin D intake on offspring asthma status is
modified by the genotypes of and the epigenetic modifications on the major regulators of vitamin D metabolism and
signaling. In Aim 1, we will determine the joint role of vitamin D binding protein (DBP) levels and vitamin D metabolism
and signaling genotypes in modulating the effect of maternal vitamin D supplementation in childhood asthma
outcomes. We will measure DBP levels in the VDAART cohort and use the existing VDAART genotyping data. We will
use Mixed Graphical Models and Conditional Gaussian Bayesian Networks to model the contribution of DBP levels,
25-hydroxyvitamin D (25-OHD) levels and vitamin D genotypes to the effect of maternal vitamin D intake on childhood
asthma, and create polygenic and polyexposure scores for individual risk prediction. In Aim 2, we will identify the
longitudinal epigenetic markers that modulate the effect of maternal vitamin D on childhood asthma. We will measure
DNA methylation on VDAART mothers pre- and post-vitamin D treatment and use existing cord blood methylation
data. We will perform epigenome-wide association studies, integrate their results with ChIP-seq and ATAC-seq data,
and perform mediation analyses to identify the longitudinal maternal epigenetic marks that potentially mediate the
effect of maternal vitamin D intake in childhood asthma. In Aim 3, we will determine the pharmacogenomic drivers of
individual differences in maternal vitamin D response and its effect on childhood asthma. We will integrate genomics,
transcriptomics and epigenomics from VDAART to identify the vitamin D-responsive pharmacogenomic expression and
methylation quantitative trait loci (PGx-eQTLs and PGx-mQTLs). We will develop a network-based statistical method to
identify the colocalization of these PGx-QTLs, perform colocalization using orthogonal approaches, and identify
endotypes through which maternal vitamin D targets childhood asthma. Within each of the above aims, we will
leverage the strong non-white representation among VDAART participants to address health disparities in vitamin D
response and asthma outcomes across the population. Our research plan is innovative in its use of highly granular
multi-omic data and cutting-edge integrative methods, and the outcomes of each aim are of high translational potential.
