<p>Several early-life environmental factors have been associated with altered risk for the development and/or severity of individual allergic conditions. These include exposures implicated in the modulation of the microbiome, such as infant delivery mode, diet, and exposure to antibiotics and antacids. The impact of these early-life factors on allergic multimorbidity remains unknown. To address this knowledge gap, we used electronic medical records for a birth cohort of 158,510 children to track development of atopic dermatitis (AD), IgE-mediated food allergy (IgE-FA), asthma, and allergic rhinitis (AR) in individual children over time. We measured hazard ratios (HRs), adjusted for birth year, race, ethnicity, sex, and insurance payer type, to assess how development of both individual and multiple allergic conditions is influenced by birth mode, feeding practice during the first year of life, or exposure to antibiotics and/or antacids during the first six months of life. We found that vaginal delivery (VD; HR 0.89, 0.83, 0.84, 0.79 for at least 1, 2, 3, 4 conditions, respectively; p≤0.001) and exclusive breastmilk (BM) feeding (HR 0.74, 0.75, 0.89, for at least 1, 2, 3 conditions, respectively; p≤0.001) are associated with reduced cumulative allergic burden, while antibiotic exposure (HR 1.40, 1.44, 1.48, 1.63 for at least 1, 2, 3, 4 conditions, respectively; p≤0.001) and antacid exposure (HR 1.26, 1.35, 1.32 for at least 1, 2, 3 conditions, respectively; p≤0.001) are associated with increased cumulative allergic burden during childhood. This work expands our understanding of how a child's early-life environment may influence their risk of allergy development and progression.</p>

<p><strong>BACKGROUND: </strong>The allergic march refers to the natural history of allergic conditions during infancy and childhood. However, population-level disease incidence patterns do not necessarily reflect the development of allergic disease in individuals. A better understanding of the factors that predispose to different allergic trajectories is needed.</p>

<p><strong>OBJECTIVE: </strong>Determine the demographic and genetic features that associate with the major allergic march trajectories.</p>

<p><strong>METHODS: </strong>Presence or absence of common allergic conditions (atopic dermatitis, AD; IgE-mediated food allergy, IgE-FA; asthma; and allergic rhinitis, AR) was ascertained in a pediatric primary care birth cohort of 158,510 subjects. Hierarchical clustering and decision tree modeling was used to associate demographic features with allergic outcomes. Genome-wide association study (GWAS) tested for risk loci associated with specific allergic trajectories.</p>

<p><strong>RESULTS: </strong>We found an association between self-identified "Black" race and progression from AD to asthma. Conversely, "Asian or Pacific Islander" race associated with AD to IgE-FA, and "White" race associated with AD to AR. GWAS of trajectory groups identified risk loci associated with progression from AD to Asthma (rs60242841), and AD to AR (rs9565267, rs151041509, rs78171803). Consistent with our epidemiologic associations, rs60242841 is more common in individuals of African ancestry (AA) than European ancestry (EA), while rs9565267 and rs151041509 are more common in EA than AA individuals.</p>

<p><strong>CONCLUSION: </strong>We identify novel associations between race and progression along distinct allergic trajectories. Ancestral genetic differences may contribute to these associations. These results uncover important health disparities, refine the concept of the allergic march, and represent a step towards developing individualized medical approaches for these conditions.</p>