Skip to main content

Research Repository

Advanced Search

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

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

Authors

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-Rodriguez

Richard Hubbard

Nik Hirani

Moira K.B. Whyte

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

R. Gisli Jenkins

Carlos Flores

Louise V Wain

Imre Noth



Abstract

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.

Citation

Oldham, J. M., Allen, R. J., Lorenzo-Salazar, J. M., Molyneaux, P. L., Ma, S. F., Joseph, C., …Noth, I. (2023). PCSK6 and Survival in Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine, 207(11), 1515-1524. https://doi.org/10.1164/rccm.202205-0845OC

Journal Article Type Article
Acceptance Date Jan 12, 2023
Online Publication Date Feb 13, 2023
Publication Date Jun 1, 2023
Deposit Date Jan 12, 2023
Publicly Available Date Feb 17, 2023
Journal American journal of respiratory and critical care medicine
Print ISSN 1073-449X
Electronic ISSN 1535-4970
Publisher American Thoracic Society
Peer Reviewed Peer Reviewed
Volume 207
Issue 11
Pages 1515-1524
DOI https://doi.org/10.1164/rccm.202205-0845OC
Keywords Idiopathic Pulmonary Fibrosis; Genome-wide Association Study; Survival; PCSK6; Protein
Public URL https://hull-repository.worktribe.com/output/4175601

Files






You might also like



Downloadable Citations