Abstract: A frequent gain of function promoter polymorphism for the PAI-1 gene (~60% of the population are homozygous or heterozygous) is associated with elevated circulating PAI-1 levels. Children homo or heterozygous for this allele who had a medically attended respiratory viral illness before age 2, had a 12 (any virus) to 18-fold (RSV) increased risk of asthma. The mechanisms for this association are not established. PAI- 1 is associated with airway thymic stromal lymphopoietin (TSLP) production, which promotes Th2 type airway responses. Furthermore, the PAI-1 overproducing genotype is associated with increased serum levels of IgE. IgE elevation increases FcεRI levels on pDCs which attenuates type I interferon antiviral responses. Of note, soy isoflavones reduce TGF-1-induced PAI-1 gene expression and protein production from airway epithelial cells, and have been shown to decrease the risk of asthma exacerbations by 70% in individuals with the genotype. It is not known whether supplementation with soy isoflavones will decrease the risk of developing Th2 airway inflammation or the likelihood of allergic sensitization if it is given to children at risk of asthma in the first year of life. Soy Isoflavones for Inner City Infants at Risk for Asthma (SIRA) is a single center, prospective randomized, quadruple masked trial of high-risk infants with the PAI-1 genotype to compare supplementation with soy genistein at doses similar to soy formula ingestion or placebo during peak viral season of the first year of life. Children aged 2-6 months at enrollment will be randomized to soy isoflavone or placebo in August, receiving active treatment from August to March 1st, followed by observation over the next year for each yearly cohort. The objective of this proposal is to determine 1) whether soy isoflavones can modulate development of Th2 airway endotypes, decrease eosinophilic airway inflammation, and reduce sensitization in high risk infants with the PAI-1 risk genotype, and 2) decrease IgE production via effects on PAI-1, and thereby improve rhinovirus-induced IFN-α response. As such, the primary outcome of the trial will be the development of T2 airway endotypes by interrupting the PAI-1/TSLP axis. Secondary outcomes will include nasal PAI-1, nasal ECP, nasal Th2 cytokine levels, serum periostin, total and specific IgE, and respiratory morbidity. The secondary aim will determine if antiviral IFN-α responses by PBMC stimulated by HRV and IgE crosslinking are augmented by soy genistein in a similar fashion as has been described for omalizumab. Secondary outcomes for this aim will evaluate if soy genistein will augment IFN-α responses by pDC in similar experiments. The current project uses a safe and inexpensive intervention, soy genistein, directed to a common genotype as a precision medicine approach to provide a better understanding of key pathways relevant to development of allergic airway inflammation in early life. If confirmatory, these results w...