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

## TL;DR

A genetic predisposition to high IgE levels defines a unique asthma type that mostly starts in adulthood, offering new ways for diagnosis and treatment.

## Contribution

A new asthma endotype is identified based on genetic predisposition to elevated IgE levels and adult-onset disease.

## Key findings

- A cluster analysis identified four asthma phenotypes, with one driven by high IgE polygenic risk scores and adult-onset type 2 inflammation.
- Over 30% of newly diagnosed asthma cases belonged to the genetically predisposed high-IgE cluster.
- Two clusters showed distinct features: one with eosinophilia and smoking-related airflow limitation, and another with a type 2 low 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 (pFEV1), 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.

The online version contains supplementary material available at 10.1038/s41598-026-37679-5.