Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease

Aspirin intolerance is a severe and relatively rare asthmatic endotype, with prevalence rates of 10% in the adult asthmatic population and up to 25% in patients with severe, persistent asthma1–4. Consistent with the classification of asthma as a set of individual subtypes of diseases of varying symptoms and severity, Aspirin Exacerbated Respiratory Disease (AERD) is distinguished from other types of severe asthma primarily by its clinical characteristics. The clinical features of AERD include airway obstruction, increased exacerbations, chronic rhinosinusitis, the presence of nasal polyps, eosinophilia, increased need for systemic glucocorticoids and poor response to asthma controller medication, and an increase in urinary leukotrienes (LTs), both in comparison to Aspirin Tolerant Asthma (ATA) and following aspirin challenge and symptom exacerbations5,6. Due to the discovery that increased production of LTs is a characteristic of AERD, the leukotriene and prostaglandin production pathways were among the first to be investigated, and the subsequent identification of polymorphisms in LT-related genes in affected patients suggested a pivotal role for genetic variation in the development of AERD6–8. As a result, variation in patient genetics has received considerable focus as a potential determinant of AERD pathogenesis. The observation that severely asthmatic subjects responded favorably to anti-leukotriene asthma medications contributed further evidence toward a mechanistic role for the LTs, while also providing an opportunity for clinicians to more appropriately tailor treatment to a specific patient group 7,9–12. Subsequent genetic studies revealed considerable evidence for genetic variation in AERD pathophysiology across multiple biological pathways7,13, as well as variation in inter-individual treatment responses to multiple asthma drug classes including leukotriene modifiers and inhibitors14. However, the exact mechanisms by which LT synthesis becomes dysregulated in AERD are still unknown. Due to corresponding alteration of immune molecules (e.g. Th2 cytokines), prostaglandins (e.g. PGE2), and other inflammatory biomarkers (e.g. IL-5, periostin, IgE, ApoA1 and others), multiple interacting pathways and mechanisms likely also contribute. Evidence that AERD has a heritable basis is minimal, and only two studies reported that 1–6% of individuals with AERD had an affected family member4,15. The adult onset of AERD, combined with the low genetic penetrance and inconsistent replication of results from genetic associations point toward involvement of environmental exposures and epigenetic factors in its progression. Achieving a better understanding of the genetic and epigenetic determinants of heterogeneity of AERD through genome-wide and epigenome-wide interrogation is therefore anticipated to improve strategies to develop more precisely tailored therapeutic agents, treatment regimens, and potentially cures, for the disease.