Association of a polygenic risk score with diagnosis and outcomes in idiopathic pulmonary fibrosis

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 health care records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic health care record diagnosis of IPF as well as lung transplant-free survival in 4 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, 1015 (2.7%), 2879 (6.5%), 1310 (3.0%), and 2742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis (odds ratio [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 (hazard ratio [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.