Genetic relationships between high blood eosinophil count, asthma susceptibility, and asthma severity

Abstract

Objective

Genetic relationships between blood eosinophil count (BEC), asthma susceptibility, and severity are unclear. We sought to identify the genetic difference between type 2 (T2) and nontype 2 (non-T2) asthma (defined by BEC) and investigate genetic relationships between high BEC, asthma susceptibility, and severity.

Methods

Genome-wide association studies (GWASs) were performed for T2 (n = 9,064; BEC ≥ 300 cells/μL) versus non-T2 asthma (n = 14,379; BEC < 150 cells/μL) and asthma susceptibility (37,227 asthmatics vs. 124,132 nonasthma controls) in the UK Biobank and asthma severity (moderate-to-severe asthma [n = 2,153] vs. mild asthma [n = 5165]) in the All of Us Research Program (AoURP). Genetic causality between BEC, asthma susceptibility, and severity were dissected using Mendelian randomization (MR).

Results

High BEC was associated with asthma and decreased pulmonary function. GWASs revealed four sets of genetic variants (p < 5 × 10⁻⁸): genes associated with only BEC or asthma and genes associated with high BEC and asthma in the same or opposite direction. The C allele of rs653178 in ATXN2 was associated with high BEC, risk for autoimmune diseases, and protection for asthma. Genetic variants associated with BEC or asthma were not associated with asthma severity. MR indicated high BEC and asthma were in bidirectional causal relationship (p < .001); however, they were not causal for asthma severity.

Conclusions

Genetic variants associated with asthma or BEC and asthma severity are distinctive. High BEC is a risk factor for asthma; however, it is neither necessary nor sufficient for asthma susceptibility and severity.

Keywords:

• All of Us Research Program
• asthma severity
• asthma susceptibility
• blood eosinophil count
• genome-wide association study
• Mendelian randomization
• UK Biobank

Acknowledgments

We acknowledge all investigators, staff, and participants in the UK Biobank and the All of Us Research Program.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was conducted using the UK Biobank Resource under Application Number 66320. This study received support from the University of Arizona-Banner Health All of Us Research Program 2022-2023 seed project program.