Decoding atopic dermatitis: patient heterogeneity and genetic variation contributing to immune-mediated dermatologic disease in the UK Biobank

Abstract

Abstract Background Dupilumab is the only approved biologic used to treat moderate to severe atopic dermatitis (AD) but has a non-response rate of 55–60%. This suggests underlying heterogeneity in AD etiology, requiring alternate therapies for patients. Study Objective Identify biomarkers and disease conditions in the UK Biobank that stratify AD patients into homogenous subgroups for genetic characterization. Methods We identified 13,137 AD cases and 13,136 age and sex-matched controls using hospital ICD9/10 and primary care codes in the UK Biobank. A total of 94 biomarkers and 1,596 disease PheCodes were used to isolate traits that vary in AD patients relative to controls; K-means (quantitative) and K-modes (binary) clustering was performed to identify subgroups within AD patients. Genetic analysis was performed for subgroups vs. controls using REGENIE. Results We observed enrichment of dermatologic, gastrointestinal, and rheumatologic conditions in AD patients, as well as differences in eosinophil percentage, Cystatin C, C-reactive protein, and erythrocyte distribution width relative to controls. There were eight subgroups of AD patients including groups with co-occurring psoriasis, asthma and gastrointestinal problems, penicillin allergy, and AD with no co-morbidities. Genetic analyses revealed novel HLA and non-HLA associations with subgroups, while also replicating known associations with FLG. Conclusion There were eight distinct AD subgroups based on co-occurring disease states. Genetic analyses show subgroup-specific factors can contribute to disease pathology—signaling potential utility for differential therapies and highlight mechanisms for targeted therapeutic development in the treatment of AD.