PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Justin M. Oldham, Richard J. Allen, Jose M. Lorenzo-Salazar, Philip L. Molyneaux, Shwu Fan Ma, Chitra Joseph, John S. Kim, Beatriz Guillen-Guio, Tamara Hernández-Beeftink, Jonathan A. Kropski, Yong Huang, Cathryn T. Lee, Ayodeji Adegunsoye, Janelle Vu Pugashetti, Angela L. Linderholm, Vivian Vo, Mary E. Strek, Jonathan Jou, Adrian Muñoz-Barrera, Luis A. Rubio-RodriguezRichard Hubbard, Nik Hirani, Moira K.B. Whyte, Simon Hart, Andrew G. Nicholson, Lisa Lancaster, Helen Parfrey, Doris Rassl, William Wallace, Eleanor Valenzi, Yingze Zhang, Josyf Mychaleckyj, Amy Stockwell, Naftali Kaminski, Paul J. Wolters, Maria Molina-Molina, Nicholas E. Banovich, William A. Fahy, Fernando J. Martinez, Ian P. Hall, Martin D. Tobin, Toby M. Maher, Timothy S. Blackwell, Brian L. Yaspan, R. Gisli Jenkins, Carlos Flores, Louise V. Wain, Imre Noth

Research output: Journal PublicationArticlepeer-review

7 Citations (Scopus)


Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 × 10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 × 10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1, 481 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 PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 × 10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. 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 plays a potentially important role in IPF progression.

Original languageEnglish
Pages (from-to)1515-1524
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number11
Publication statusPublished - 1 Jun 2023
Externally publishedYes


  • IPF
  • PCSK6 protein
  • genome-wide association study
  • genomics
  • survival

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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