Exploration of Asthma Phenotypes Associated With Genetic Determinants of Total Serum IgE Levels

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Abstract Rationale: Elevated total serum IgE levels are associated with asthma independent of allergen sensitization, suggesting a role for genetic factors regulating IgE levels in asthma pathogenesis. This study aimed to characterize asthma phenotypes in adults that are influenced by genetic factors associated with elevated total IgE levels. Methods: This study population comprised Japanese adult healthy controls (N=1379) and adult asthma patients (N=750). We performed a genome-wide association study (GWAS) of total IgE levels in healthy adults without asthma or atopic dermatitis and developed a polygenic risk score (IgE_PRS) for total serum IgE using PRSice-2 with clumping and thresholding method. This IgE_PRS was then calculated in adult asthma patients using the same SNP set. A two-step cluster analysis was performed in asthma patients based on total serum IgE, pFEV1, age at asthma onset, and IgE_PRS to delineate distinct clusters. In addition, we evaluated the distribution of these clusters among newly diagnosed asthma cases in a 10-year prospective cohort of Japanese healthy adults (N=1303) using a decision tree model to validate the cluster distribution. Results: IgE_PRS was derived from 16,169 SNPs, and showed the strongest association with total IgE levels (p=0.0018, r2=0.017) but not with allergen sensitization (p=0.595) in healthy adults. Total IgE levels were significantly elevated in asthmatic patients compared to healthy controls (p=2.4×10-25), while IgE_PRS levels were not significantly different between groups (p=0.235). The two-step cluster analysis of asthmatic patients identified four distinct subgroups, two of which had significantly higher IgE_PRS compared to healthy controls. Cluster 1 (N=194), with the highest IgE_PRS, was characterized by adult-onset allergic asthma, elevated total IgE levels, high allergen sensitization (75.3%), mild airflow obstruction, and a predominance of females (64.4%). Cluster 2 (N=172), with the second highest IgE_PRS, included individuals with adult-onset asthma, moderate to severe airflow obstruction, and a high prevalence of smoking (52.3%). Of 79 newly diagnosed asthma cases, 26.6% were classified in the highest IgE_PRS cluster. Conclusions: Our findings reveal a distinct phenotype of adult-onset asthma characterized by a genetic predisposition to elevated total IgE levels. This study highlights the potential of IgE_PRS-driven clustering to identify asthma endotypes that may be particularly influenced by genetic susceptibility to high IgE levels, with implications for more tailored therapeutic approaches.

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