Genetic predisposition to elevated total immunoglobulin E levels defines a distinct adult-onset-predominant asthma phenotype

Abstract Asthma heterogeneity remains a major barrier in precision medicine. Although elevated total serum immunoglobulin E (IgE) is a hallmark of asthma, even in nonatopic patients, its causal role in asthma pathogenesis is debated. We hypothesized that genetic predisposition to increased IgE defines a distinct asthma endotype. A genome-wide association study of total serum IgE in 1,287 non-asthmatic Japanese adults was used to construct IgE polygenic risk scores (IgE_PRS). Applying IgE_PRS to 745 patients with asthma, we performed cluster analysis incorporating age at onset, total IgE levels, IgE_PRS, and percent predicted forced expiratory volume in 1 s (pFEV 1 ), identifying four distinct adult asthma phenotypes. Notably, one cluster had the highest IgE_PRS and adult-onset-predominant type 2 inflammation. Conversely, the second cluster displayed the highest IgE levels but average IgE_PRS. The remaining two clusters comprised patients with lower IgE_PRS. One cluster was characterized by eosinophilia and smoking-related airflow limitation, whereas the other exhibited a type 2 low phenotype. In a 10-year retrospective cohort, over 30% of newly diagnosed asthma cases fell into the genetically predisposed high-IgE_PRS cluster. These findings reveal a distinct adult-onset-predominant asthma phenotype driven by genetically determined IgE production, offering new avenues for endotype-driven diagnosis and personalized therapy.