Association of a Polygenic Risk Score with Diagnosis and Outcomes in Idiopathic Pulmonary Fibrosis

作者：S. Kalra, Christopher Grilli, Brandon J. Coombes, Sebastian M. Armasu, D Upjohn, Jan B. Egan, Qingwen Chen, Courtney Tern, Chengyue Zhang, Jonathan A. Rose, Rachel Putman, Greg McDermott, Yuli Lily Hsieh, Michele L. Bublitz, Eva M. Carmona, Eric W Klee, K Lazaridis, Jessica Lasky‐Su, Frank Dudbridge, Anna L. Peljto, D A Schwartz, Edwin K. Silverman, Richard J. Allen, Janet Olson, T Walker, Louise V. Wain, Ana C. Zamora, Joe Zein, Gary M. Hunninghake, V E Ortega, Tapestry Cohort, Matthew Moll, Michael H Cho · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2026 · DOI：10.1093/ajrccm/aamag271 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Systemic Sclerosis and Related Diseases、Lung Cancer Treatments and Mutations

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:...