Lazaridis, K

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

Abstract Rationale Asthma contributes substantially to healthcare burden and morbidity through frequent exacerbations. Emerging evidence suggests that genetic factors play a crucial role in modulating susceptibility to asthma exacerbations. To better understand the genetic architecture of exacerbations, we conducted a genome-wide association study (GWAS) in the Tapestry cohort. Methods The Tapestry Study, a large-scale, decentralized and clinical grade genomic sequencing study, conducted Exome+® sequencing at Helix, Inc. on 98,075 Mayo Clinic participants. After excluding patients with ≥10 pack-years of smoking and/or emphysema, we performed a GWAS of asthma exacerbations in 3,960 adults with asthma based on ICD codes. Cases (n = 1,059) were defined as individuals who experienced at least two exacerbations between 2020 and 2025; the remaining 2,901 individuals served as controls. Asthma exacerbations were defined by oral or systemic corticosteroid prescriptions with durations ranging from 3 days up to 28 days. Logistic regression models adjusted for age, sex, BMI, and the first six principal components of ancestry. Replication was performed in 1,273 asthma patients (439 African Americans and 834 non-Hispanic Whites) from the NHLBI-sponsored Severe Asthma Research Program (SARP 1-3), with adjustments for age, sex, BMI, and the first 10 principal components of ancestry. Results Based on a minor allele frequency (MAF) threshold of > 0.05, we analyzed 5,256,135 genome-wide variants. Genome-wide significant associations for asthma exacerbations (p < 5.0 × 10⁻8) included loci at a pseudogene in SMPD4P1 (rs680548, MAF = 0.39, OR = 1.37, p = 9.10 × 10⁻9). Additional variants showing suggestive associations included loci within ENDOD1 (rs638776, OR = 0.69, p = 1.20 × 10⁻6), PCSK2 (rs2206454, OR = 1.32, p = 3.53 × 10⁻6), RBFOX1 (rs17667084, OR = 0.60, p = 5.11 × 10⁻6), and CDC42EP3 (rs721660, OR = 1.29, p = 5.68 × 10⁻6). Subthreshold associations in Tapestry including loci at CDC42EP3 (rs4670213, OR = 1.27, p = 1.41x10-5, MAF = 0.36), and SDR39U1 (rs12587663,OR = 0.83, p = 5.86x10-4, MAF = 0.46) were replicated in the SARP longitudinal visit 5 with p-values of 8.523x10-3 (rs4670213, OR = 1.78), and 2.88x10-4 (rs12587663,OR=0.43), respectively. Conclusion Our GWAS for asthma exacerbations in the Tapestry cohort identified variant loci relevant to mitophagy mechanisms (CDC42EP3, PMID: 40783597), immune signaling and RNA splicing regulation (RBFOX1, PMID: 31301374), and neuromodulatory pathways (PCSK2, PMID: 32794589), all previously implicated in asthma pathophysiology. Collectively, these findings highlight potential novel genetic contributors to asthma exacerbations and provide a foundation for improving risk stratification and therapeutic targeting in asthma management. This abstract is funded by: This abstract is funded by: Mayo Clinic Funding: X01 from the NHLBI for TOPMed whole-genome sequencing and NIH grants R01 HL142992, HL69116, HL69167, HL69170, HL69174, U10 HL109164, U10 HL109257, U10 HL109146, U10 HL109172, U10 HL109250, U10 HL109250, U10 HL109250, U10 HL109168, U10 HL109152, U10 HL109086, U10 HL109046.