LAUSR

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. Novel therapies and prognostic biomarkers are needed. Objective: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Main Results: After quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma and negatively correlated with survival. Peripheral blood PCSK6 gene expression and plasma concentration were associated with reduced transplant-free survival. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein may serve as prognostic biomarker in IPF and potential therapeutic target.