Asthma exacerbations and eosinophilia in the UK Biobank: a Genome-Wide Association Study

Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g.:T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. UK Biobank data were used to perform a GWAS study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalization data and General Practitioners (GP) records. Exacerbations were identified as either asthma-related hospitalization, GP record of asthma exacerbation, or an oral corticosteroid (OCS) burst prescription. A logistic regression model adjusted for age, sex, smoking status, and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (P<5x10-6) in the GERA cohort. In the UK Biobank, we identified 11,604 cases, and 37,890 controls. While no variants reached genome wide significance (P<5x10-8) in the primary analysis, 116 signals were suggestively significant (P<5x10-6). In GERA, two SNPs (rs34643691 and rs149721630) were nominally significant and showed the same direction of effect. Two novel genetic loci-(NTRK3 and ABCA13)-that are reproducibly associated with asthma exacerbation in participants with asthma were identified. Confirmation of these findings in different asthma (or ancestry) sub-populations and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.