Aspirin-exacerbated respiratory disease is associated with variants in filaggrin, epithelial integrity, and cellular interactions

Abstract

BackgroundPrevious studies identified upto 6% of patients with Aspirin-Exacerbated Respiratory Disease (AERD) have family history of AERD indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking. ObjectivesWe sought to examine whether WES can identify pathogenic variants associated with AERD. MethodsAERD diagnosis was confirmed in patients with nasal polyps and asthma. WES was performed using an Illumina sequencing platform. Human Phenotype Ontology (HPO) terms were used to define the patients’ phenotypes. Exomiser was used to annotate, filter, and prioritize possible disease-causing genetic variants. ResultsAmong thirty-nine patients with AERD, 41% reported a family history of asthma and 5% a family history of AERD. Pathogenic exome variants in the filaggrin gene (FLG) were found in two patients (5%). Other variants not known to be pathogenic were detected in an additional 16 patients (41%) in genes related to epithelial integrity and cellular interactions, including genes encoding desmoglein 3 (DSG3), dynein axonemal heavy chain 9 (DNAH9), collagen type VII alpha 1 chain (COL7A1), collagen type XVII alpha 1 chain (COL17A1), chromodomain helicase DNA binding protein-7 (CHD7), TSC complex subunit 2/tuberous sclerosis-2 protein (TSC2), P-selectin (SELP), and platelet-derived growth factor receptor-alpha (PDGFRA). ConclusionWES identified a monogenic susceptibility to AERD in 5% of patients with FLG pathogenic variants. Other variants, not previously identified as pathogenic, were found in genes relevant to epithelial integrity and cellular interactions and may further reveal genetic factors that contribute to this condition.