Integrative-omics and Systems Biology across the atopic march

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Summary: The atopic march is the natural history of atopic manifestations representing a sequence of atopic disease through life course; AD is considered the “entry point” for subsequent allergic disease and can predispose infants and children to other atopic diseases, including food allergy, allergic rhinitis, and allergic asthma. While the concept may be an oversimplification of the process within a single individual, epidemiological studies support a causal relationship between AD and other atopic diseases. In fact, when one looks to genetics across these phenotypes, we see tremendous overlap in the genomic determinants across these traits; the greatest connectivity being between food allergy and AD followed by AD and asthma with genes pertaining to immunity and barrier function being focal hubs. A comprehensive understanding of allergy is dependent on our interpretation of molecular intricacy and multi-omics variation, and this project aims to bring together a variety of omics (genetics, epigenetics, transcriptomics and proteomics) across the allergic diathesis with the overall goals of (1) understanding the genetic signatures that can be leveraged in clinical translation for allergy; (2) understanding mechanism of disease and disease severity to facilitate clinical translation through disease endotyping; and (3) bring about health equity by the inclusion of all populations bearing the burden of allergic disease in these systems biology studies pertaining to the allergic diathesis. In FY2025 we have expanded our established repository of multi-omics data within the GPHS. Previously our work was focused on The Consortium on Asthma among African-ancestry Populations in the Americas - CAAPA for asthma, The Atopic Dermatitis Research Network - ADRN for AD, and three oral immunotherapy clinical trials for peanut allergy - LEAP, IMPACT and POISED; all of which that have genetics coupled with deep phenotyping. In FY2025 we have expanded our genetics repository now to include LEAP-Trio – the 10 year follow up and the family members from the original LEAP study focused on oral immunotherapy for peanut allergy, CATNIP (combination treatment with tezepelumab and allergen immunotherapy for aeroallergens), GRADUATE (sublingual immunotherapy or SLIT with Dupilimab for aeroallergens), GRASS (SLIT alone for aeroallergens) and OUtMATCH (anti-IgE for food allergy). Importantly, we have expanded our omics data repositories to include proteomics and Methyl-Seq assays, and we have initiated investigations using the publicly available All of Us data. Asthma: A recent publication by our group in Nature communications (May 2024) revealed gene networks in nasal epithelium target tissue representing molecular dysregulation on three distinct axes – increased Th2 inflammation, decreased capacity for wound healing and increased airway remodeling, and impaired drug response – that may play a critical role in asthma within the African Diaspora. These three separate axes of risk offer promise that multi-omics data may help refine asthma endotypes that can then be implemented within a Precision Health framework to refine individualized therapy especially with biologics. Prior transcriptomics work in CAAPA was at the gene-based level and in FY2025 we have transitioned to a cutting-edge transcript-based bioinformatic approach on bulk RNA-Seq data from nasal epithelium honing on new findings around alternative splicing of genes related to airway remodeling that continue to implicate this axis of decreased capacity for wound healing and airway remodeling in asthma. In FY2025 we completed the analysis of bulk RNA-Seq on PBMCs from CAAPA study subjects to examine the role of systemic (PBMC) signatures for asthma. We identified dozens of differentially expressed genes and identified 31 upstream regulators including well-known T2 cytokines in asthma as well as miRNAs previously shown to play a role in epithelial cell dysfunction. Our work on PBMCs confirm that they are an important target tissue largely capturing systemic signatures related to inflammatory signaling in asthma. This contrasts with the nasal epithelium which additionally captures signatures of dysregulation related to local medication (e.g., inhaled corticosteroids) and impaired airway wound healing. In FY2025, we have generated proteomics profiles on ~500 CAAPA study subjects using the SomaScan® 11K Assay. These data will be used to identify proteomic signatures for asthma and multi-omics assessments of asthma severity in the future. Asthma endotypes entail dynamic airflow impairment shaped by genetic, inflammatory, and environmental factors. Despite advances, >50% of US asthma remains uncontrolled, with 80% classified as mild/moderate—highlighting critical under-treatment and misclassification. In FY2025 we have expanded these approaches to map transcriptomic drivers of “asthma control” modeling asthma severity as a continuous scale of "distance from control" and our findings implicate estrogen in worsening asthma control via Th2-inflammatory and metabolic pathways. We are currently expanding our findings leveraging the All of Us database. Allergy: In FY2025, we completed our study on the genetic determinants of peanut-specific IgG4 levels in the context of sustained oral peanut exposure in the LEAP study. Identification of the SEPT2 locus in participants protected from peanut allergy (PA) suggests involvement of epithelial-barrier pathways in modulating immune responses. Findings across all several trials emphasize the importance of gene*environment interactions, specifically the interplay between genetics and oral peanut exposure. Taken together, the findings indicate that early, sustained peanut consumption, combined with genetic factors, promotes a protective immune response to peanut allergens. In FY2025 we have completed the genotyping of an additional ~1000 LEAP-trio study subjects which will allow us to expand our hypotheses to siblings of the index LEAP participants in the future. We have also successfully set up four new collaborations and have initiated the genotyping for four clinical trials in the space of food and aeroallergen allergy: (i) OUtMATCH clinical trial asseses the role of genetics in response to anti-IgE therapy in managing muti-food allergy; (ii) CATNIP (combination treatment with tezepelumab and allergen immunotherapy for aeroallergens), (iii) GRADUATE (sublingual immunotherapy or SLIT with Dupilimab for aeroallergens), (iV) GRASS (SLIT alone for aeroallergens). We have previously published on the prominent role for gene*environment signatures in the MALT1 and HLA-DQA1 genes for peanut allergy in the LEAP clinical trial. In FY2025 we have undertaken a mechanistic follow up for these findings. We are currently performing a genomewide Methyl-Seq assay on 67 samples including baseline and post-intervention to determine if the interaction effect is driven by methylation changes that account for gene expression changes. Public Data Sharing: In FY2025 we migrated the Omics Analysis, Search & Information System (OASIS) from its original location at the University of Maryland to NIAID’s Monarch Spaces AWS platform for web applications. The migration included transfer of three terabytes of data from GPHS-led genomics interrogations of allergy to the AWS-based relational database system (RDS). All software used in the OASIS application was upgraded to the most recent version and scanned to ensure that all security standards were met. OASIS enables discovery by allowing researchers to mine results from omics association studies. This web-based, searchable database system integrates association analysis results with annotation, bioinformatics resources, real-time data visualizations. Integrated, supplementary analysis tools help to elucidate additional biological insights. OASIS now contains summary statistics on 92 GWAS for allergy, integrates seamlessly with external databases (e.g. UKBB, GTEx, UCSC genome browser) and allows for multiple analysis options on the fly (e.g. linkage disequilibrium, colocalization, variant annotation). OASIS is available to NIH and non-NIH academic researchers globally via our account approval and access control processes.