C94-03 Linking Airway Biology to Systemic Health: A PheWAS of BPIFA1 Variants in the All of Us Cohort

Abstract Rationale The BPIFA1 gene encodes BPI Fold Containing Family A Member 1, a secreted protein abundantly expressed in lung lining fluid. BPIFA1 regulates mucociliary clearance and inflammation by binding to plasma membrane ion channels. Loss of BPIFA1 function contributes to asthma, COPD, and cystic fibrosis disease severity, highlighting its critical role in lung health. BPIFA1 is also highly expressed in other tissues (e.g., saliva, reproductive, thymus, liver, kidney, heart, etc.) where its systemic functions remain poorly understood. Identifying extrapulmonary diseases linked to BPIFA1 variants is crucial, as immune, endocrine, and metabolic pathways may modify airway inflammation, infection susceptibility, and treatment response. Our objective was to map systemic and pulmonary consequences of BPIFA1 variation using the “All of Us” cohort with the goal of identifying novel biomarkers and therapeutic opportunities in lung disease. Methods We performed a phenome-wide association study (PheWAS) using whole genome sequencing and linked electronic health record (EHR) data from 414,830 participants from the All of Us cohort CDR v8. Single nucleotide variants within the BPIFA1 locus were extracted and underwent rigorous quality control. Phenotypes were derived from EHR data mapped to standard phecodes using the PheTK python library, where a patient must have 2 occurrences of an ICD code to be assigned a phecode. Only phecodes with a minimum of 200 cases were included in the analysis. Logistic regression models were used to test associations between BPIFA1 variants and phecodes, adjusting for age, sex, race, and population stratification. Multiple testing was addressed using false discovery rate correction, and significant findings (Q 2.5E-5) were examined for relevance to lung and systemic disease. Results A total of 307 variants remained for analysis after quality control. A total of 1,843 phecodes were tested for association with the 307 BPIFA1 variants. Across these variants, we consistently observed significant (p 10-9) associations between BPIFA1 and phecodes pertaining to lung disease such as abnormal chest sounds, disorders of the diaphragm, and chronic airway obstruction. The top extrapulmonary conditions significantly associated with BPIFA1 variants included known extrapulmonary conditions associated with lung disease (e.g., osteoporosis, conjunctivitis, glycosuria, cachexia, and intestinal ischemia). Conclusions Our findings have broadened our understanding of the systemic consequences of BPIFA1 variation and revealed novel disease pathways converging on lung health through immune, endocrine, or metabolic mechanisms. These associations may extend the therapeutic relevance of BPIFA1-targeted interventions beyond classical airway diseases, highlighting opportunities to ameliorate extrapulmonary conditions that exacerbate respiratory morbidity and progression. This abstract is funded by: none