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.
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Data availability
The GWAS genotype data of the non-asthmatic controls and asthma patients collected by our group at the University of Tsukuba cannot be deposited in a public repository, since no consent was obtained for deposition ***. However, these data are available upon request (contact: nhizawa@md.tsukuba.ac.jp) for use in research on inflammatory lung diseases.***.
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Acknowledgements
We thank Ms. Takako Nakamura for her assistance with the genotyping.
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T.M., H.M., and N.H. organized and designed the study. T.M., H.M., Y.O., R.S., H.K., Y.Y., and N.H. participated in sample collection and contributed to data analysis.T.M., H.M., and N.H. drafted the manuscript. All the authors have read and approved the final manuscript.
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This study was approved as part of the research project titled “Genetic Predisposition to Inflammatory Obstructive Pulmonary Diseases” (a human genome and gene analysis research project) by the Institutional Review Boards (IRBs) of the University of Tsukuba (IRB No. 136-4) and the University of Tsukuba Hospital (IRB No. H29-294).
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Written informed consent was obtained from all participants, and all procedures were conducted in accordance with the Ethical Guidelines for Human Genome/Gene Analysis Research established by the three ministries of the Japanese government.
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Matsuda, T., Masuko, H., Ozawa, Y. et al. Genetic predisposition to elevated total immunoglobulin E levels defines a distinct adult-onset-predominant asthma phenotype. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37679-5
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DOI: https://doi.org/10.1038/s41598-026-37679-5
