Refining the Atopic March: Mechanisms of Progression in Black and White Children

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Project Summary For nearly two decades, the “atopic march” concept, which describes the sequential development of atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) has served as a guiding principle, however, a recent NIH workshop concluded that only about 3% of children follow the traditional atopic march. They stated that while early-life AD remains a major risk factor for the development of any atopic disease, there is no single unique pathway for the atopic march. Rather, there is significant heterogeneity including the timing and organ(s) affected, and the march needs to be revised to include this heterogeneity and incorporate the various combinations. We designed the Mechanisms of Progression of Atopic Dermatitis (AD) to Asthma in CHildren (MPAACH) cohort, the first US prospective longitudinal early life cohort of AD, to meet this need. MPAACH includes 65% Black children and is one of the only early life cohorts that represents this historically underrepresented and understudied population. Previous studies of the atopic march were done mostly in White populations. Our early findings from MPAACH reveal marked racial differences in the atopic march concept and underscore the racial bias in current paradigms around the atopic march. Black children are disproportionately impacted by asthma prevalence, morbidity, and mortality and this race-asthma association is not eliminated after adjusting for socioeconomic factors suggesting that race may also serve as a proxy for a critical biologic factor that we do not currently recognize. Our central hypothesis is that the longitudinal trajectories of sensitization and allergic disease progression are different between Whites and Blacks, and that this is mechanistically due, in part, to biologic differences. We will conduct skin transcriptomics and integrate this data with longitudinal immunologic, environmental, and clinical data to construct the pathogenesis of allergic disease development, progression, persistence, remission, and resolution. Race is a complex concept including sociocultural and socioeconomic, as well as biologic factors. As such, we will define Black and White using self-reported race, genetic ancestry, and biologic methods that quantify melanin content in the skin, thus recognizing the continuum resulting from biologic diversity in addition to the sociocultural definitions of race. This application will have significant public health impact. Through the proposed aims, we will (1) define longitudinal AD phenotypes in Black and White MPAACH children, (2) elucidate skin transcriptomic profiles and biologic pathways that predict AD longitudinal phenotypes for Black and White MPAACH children and (3) define longitudinal immunophenotypes of AD in Black and White children and construct the pathogenesis of allergic disease by race based on genetics (from Project 2)--> skin transcriptomics--> immunologic milieu--> longitudinal clinical endotypes.