Incorporating genetics in identifying peanut allergy risk and tailoring allergen immunotherapy: A perspective on the genetic findings from the LEAP trial

Examining the genetics of peanut allergy (PA) in the context of clinical trial interventions and outcomes provides an opportunity to not only understand gene-environment interactions for PA risk but to also understand the benefit of allergen immunotherapy. A consistent theme in the genetics of food allergy is that in keeping with the dual allergen exposure hypothesis, barrier- and immune-related genes are most commonly implicated in food allergy and tolerance. With a focus on PA, we review how genetic risk factors across 3 genes (FLG, MALT1, and HLA-DQA1) have helped delineate distinct allergic characteristics and outcomes in the context of environmental interventions in the Learning Early about Peanut Allergy (LEAP) study and other clinical trials. We specifically consider and present a framework for genetic risk prediction for the development of PA and discuss how genetics, age, and oral consumption intertwine to predict PA outcome. Although there is some promise in this proposed framework, a better understanding of the mechanistic pathways by which PA develops and persists is needed to develop targeted therapeutics for established disease. Only by understanding the mechanisms by which PA develops, persists, and resolves can we identify adjuvants to oral immunotherapy to make older children and adults immunologically similar to their younger, more malleable counterparts and thus more likely to achieve long-term tolerance.