Abstract Rationale Prior studies on genetic mutations in asthma have primarily focused on heritability-associated mutations in pediatric populations. Although genome wide association studies have evaluated genetic risk factors for asthma, fewer studies have targeted severe asthma patients, with less focusing on mutations in immune regulatory pathways or rare variants. The Invitae Primary Immunodeficiency (PID) panel is a clinically available genetic screen identifying exon-specific single nucleotide polymorphisms in 429 genes with previous links to immunodeficiency. We hypothesized that patients with complex severe asthma would exhibit increased frequency of these SNPs compared to general population controls. Methods Data from sixty-nine severe asthmatic airway disease (SAAD) patients seen in an adult asthma clinic at the University of Pittsburgh Medical Center who were administered the Invitae PID panel for clinical reasons was analyzed, with frequency of pathogenic and variants of uncertain significance (VUSs) compared to population databases. Results The median age was 62 years interquartile range [IQR 47-69 years]; 71% were female and 90% white. All patients had spirometric evidence of airway obstruction, 50% had a co-existing autoinflammatory condition (including Rheumatoid arthritis), 40% had history of hypogammaglobulinemia/recurrent infections. Patients had a median of 2 mutations IQR 1-4, with 21 (30%) having 4 mutations. . Thirty-nine (9%) of these 429 genes were mutated in ≥ 2 patients. The most frequently mutated gene was NOD2, in 10 patients. Six had the C. 3019duo (p. Leu1007Proofs*2) and 4 had the c. 2104CT (p. Arg702Trp) mutations, with a frequency of 9% and 6% in this cohort (overall population frequency of 1-3%). Mutations in Adaptor related protein complex3 AP3D1, facilitating vesicle budding from the golgi, were seen in 6 with 2 having the same exon 22, c. 2593₂598del (p. Glu865Lys866del) mutation; population frequency unknown/unreliable. Four patients had mutations in Hypoxia upregulated protein-1 HYOU1, an endoplasmic reticulum molecular chaperone, with 2 having the same c. 2638GA (p. Ala880Thr) mutation for a frequency of 3% vs. 0. 07% in the general population. Four had unique mutations in NLRP12, an inflammasome related gene, and another 4 patients had unique mutations in ERBB2 interacting protein ERBIN, involved in cellular signaling. None of these VUS had a frequency in population genetic databases of ≥ 0. 01%NLRP12 and ≥0. 1%ERBIN. Conclusions Immunodeficiency mutations were strikingly common in a small population of patients with complex and difficult to control asthmatic airway disease, often 100-1000 times more common than in general population databases. These data suggest that in older adults with SAAD, gene by environment interactions may contribute to their poorly understood disease. This abstract is funded by: none
Fajt et al. (Fri,) studied this question.