Weaver, Marianna

Abstract Purpose Bronchiectasis is a condition characterized by chronic cough, recurrent infections, and progressive airway damage that is rising in prevalence. While often idiopathic, a subset of patients have a genetic cause such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), or alpha-1-antitrypsin deficiency (A1ATD). Genetic causes for bronchiectasis should be considered in patients with diffuse bronchiectasis involving ≥2 lobes, especially in those with early onset of symptoms, recurrent otitis media or chronic rhinosinusitis, infertility, organ laterality defects (e.g., situs inversus), exocrine pancreatic insufficiency or family history of bronchiectasis. Genetic testing may impact management decisions. Methods The Mayo Clinic Center for Individualized Medicine developed the Program for Rare and Undiagnosed Diseases (PRaUD) Genetic Testing and Counseling Unit (GTAC) provides abbreviated, point-of-care genetic counseling, and DNA sequencing-based testing. Patients with bronchiectasis evaluated by GTAC underwent exome or genome-based 52-gene panels which included PCD, CF, and A1ATD (SERPINA1)-associated genes. Sequencing panes results were reviewed and interpreted by a multidisciplinary team including genetic counselors, geneticists, and pulmonologists. Results From July 2022 to December 2025, 203 patients were identified; 163 patients completed testing (74% female, 93% white). A molecular diagnosis was confirmed in 10.4% (17/163) of cases, with known pathogenic variants identified in RSPH4A, SERPINA1 (A1ATD), and CFTR (CF). Variants of uncertain significance (VUS) were identified in 24% of patients. Notably, 11.6% (19/163) were identified as CF carriers, a rate significantly higher than the general European-ancestry population (∼4%). Clinical management was impacted for two patients, including the initiation of targeted CFTR modulator therapy in one patient with CF-related disorder (CFTRD) and one CFTR pathogenic variant heterozygote. Conclusions Genetic counselor-supported DNA sequencing for bronchiectasis led to an increased identification of genes that cause bronchiectasis. Interestingly, we found a high rate of CFTR heterozygote variant carriers in our clinic cohort, this aligns with the findings of other studies that CFTR variant carriers can have an increased frequency of bronchiectasis. The identification of pathogenic variants and VUS helps facilitate a diagnosis or potential genetic cause in a significant proportion of patients and highlights the need for further research in understanding the epidemiology of CF, PCD, and A1ATD-related variant genotypes in patients with bronchiectasis. Clinical Implications Comprehensive DNA sequencing, combined with genetic counseling and support from genetic counselors in partnership with pulmonologists can advance precision diagnostics and care for patients with bronchiectasis. This abstract is funded by: None

Abstract Rationale Glucagon-like peptide 1 (GLP-1) receptor agonists are novel antihyperglycemic drugs that have shown benefit in various disease states, namely in cardiovascular and renal disease. GLP-1 agonists in murine models of obstructive lung diseases have been shown to decrease airway inflammation and hyperresponsiveness. In humans, some observational studies show an association between GLP-1 agonist use and reduced exacerbations of chronic obstructive pulmonary disease (COPD). In a meta-analysis, GLP-1 agonist use decreased the risk of several respiratory disorders including bronchitis (3). Bronchiectasis is another chronic airway disease, characterized by abnormal airway dilation leading to impaired mucous clearance and increased risk of infection (4). Data on the association between GLP-1 agonist use and bronchiectasis is sparce. We, therefore, examined the effects of GLP-1 agonists on the mortality of patients with bronchiectasis in a large sample size. Methods In this retrospective case control study, we identified patients with bronchiectasis from a single-center database of patients at our institution. We identified patients with bronchiectasis who received a GLP-1 agonist and compared them to patients who never received a GLP-1 agonist. Data was displayed as median with interquartile range and a Kaplan-Meier curve was used for mortality analysis. Results We identified a total of 256,777 patients with bronchiectasis. Of these, 249911 patients with bronchiectasis had not received a GLP-1 agonist and 6866 patients had received a GLP-1 agonist. The median age for patients in the GLP-1 group was 63 vs. 64 for the control group. 54.5 % of patients in the GLP-1 group were female compared to 52.9% in the control. Patients who received a GLP-1 agonist had improved survival at 1 month (99.9% for the GLP-1 group vs. 98.7% for the control group), 5 months (98.9% for the GLP-1 group vs. 95.9% for the control group), 10 months (97.9% for the GLP-1 group vs. 93.5% for the control group), 30 months (91.9% for the GLP-1 group vs. 86.8% for the control group) and 60 months (81.8% for the GLP-1 group vs. 79.3% for the control group), p < 0.001, Hazard ratio 0.56 (95% CI 0.50 - 0.62). Conclusion Our study showed that GLP-1 agonists are associated with improved survival in patients with bronchiectasis. Several mechanisms may contribute to this effect, including weight loss and reduction of cardiovascular mortality. Further studies are needed to investigate GLP-1 agonists as a potential therapeutic option for bronchiectasis, and to elucidate the mechanisms behind this association. This abstract is funded by: none