BRIEF RESEARCH REPORT article
Front. Allergy
Sec. Genetics and Epidemiology
Volume 6 - 2025 | doi: 10.3389/falgy.2025.1670783
Machine Learning–Derived Genetic Risk Scores Identify IL21 as a Predictor of Response to Omalizumab and Dupilumab in Asthma
Provisionally accepted
- Brigham and Women's Hospital, Harvard Medical School, Boston, United States
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ABSTRACT Rationale: Genetic risk scores (GRS) of Th1/2/17-related loci may be associated with response to biologics. We leveraged previously published machine learning-derived GRSs associated with plasma proteins from the INTERVAL/UK-Biobank study. Methods: We assessed 42 Th1/2/17-related GRSs and SNPs for association with response (≥50% reduction in exacerbations) to biologics in 172 White patients with moderate-to-severe asthma in the Mass General Brigham Biobank (MGBB: 92 omalizumab, 38 mepolizumab, 42 dupilumab). Replication was sought in 243 individuals in the All of Us (AoU) cohort (111 omalizumab, 58 mepolizumab, 74 dupilumab). Models adjusted for age, sex, BMI, baseline exacerbations, and principal components 1–10. AUROC was used to evaluate top predictors; type I error was assessed using random GRS sets (target FDR ≤20%). Results: Females comprised a large proportion; mean BMI was 28–35 kg/m². IL21 GRS was associated with omalizumab response in MGBB (OR 1.7, 95% CI 1.03–2.87) with similar direction in AoU (1.5, 0.91–2.45). IL21 also predicted dupilumab response in MGBB (2.4, 1.05–5.44) but in the opposite direction in AoU (0.57, 0.31–1.06). IL21 replicated as a predictor of omalizumab (AUROC, 95% CI: MGBB 0.62 (0.50 – 0.74), AoU: 0.71 (0.61 – 0.81)) and dupilumab (AUROC, 95% CI, MGBB 0.76 (0.58 – 0.95), AoU: 0.75 (0.64 – 0.86)). Adding IL5RA (omalizumab) or CCL17 (dupilumab) modestly improved AUROC but not significantly. No GRS predicted mepolizumab response. Conclusions: Using ML-based GRS applied to an independent cohort of asthma patients, we found that IL-21-related GRSs were predictors of response to omalizumab and dupilumab.
Keywords: Asthma, Mepolizumab, Dupilumab, Omalizumab, biomarkers, Genetic risk score, Il-4r, IL-5
Received: 22 Jul 2025; Accepted: 15 Sep 2025.
Copyright: © 2025 Akenroye, Zhang, Nopsopon, Kalra, Weiss and Moll. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ayobami Akenroye, aakenroye@bwh.harvard.edu
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