Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

Richard J Allen; Justin M Oldham; David A Jenkins; Olivia C Leavy; Beatriz Guillen-Guio; Carl A Melbourne; Shwu-Fan Ma; Jonathan Jou; John S Kim; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative; William A Fahy; Eunice Oballa; Richard B Hubbard; Vidya Navaratnam; Rebecca Braybrooke; Gauri Saini; Katy M Roach; Martin D Tobin; Nik Hirani; Moira K B Whyte; Naftali Kaminski; Yingze Zhang; Fernando J Martinez; Angela L Linderholm; Ayodeji Adegunsoye; Mary E Strek; Toby M Maher; Philip L Molyneaux; Carlos Flores; Imre Noth; R Gisli Jenkins; Louise V Wain

doi:10.1016/S2213-2600(22)00251-X

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

Lancet Respir Med. 2023 Jan;11(1):65-73. doi: 10.1016/S2213-2600(22)00251-X. Epub 2022 Aug 16.

Authors

Richard J Allen¹, Justin M Oldham², David A Jenkins³, Olivia C Leavy⁴, Beatriz Guillen-Guio⁴, Carl A Melbourne⁴, Shwu-Fan Ma⁵, Jonathan Jou⁶, John S Kim⁵; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative; William A Fahy⁷, Eunice Oballa⁷, Richard B Hubbard⁸, Vidya Navaratnam⁹, Rebecca Braybrooke⁸, Gauri Saini¹⁰, Katy M Roach¹¹, Martin D Tobin⁴, Nik Hirani¹², Moira K B Whyte¹², Naftali Kaminski¹³, Yingze Zhang¹⁴, Fernando J Martinez¹⁵, Angela L Linderholm¹⁶, Ayodeji Adegunsoye¹⁷, Mary E Strek¹⁷, Toby M Maher¹⁸, Philip L Molyneaux¹⁹, Carlos Flores²⁰, Imre Noth⁵, R Gisli Jenkins²¹, Louise V Wain²²

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, UK. Electronic address: rja34@leicester.ac.uk.
² Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
³ Division of Informatics, Imaging & Data Sciences, University of Manchester, Manchester, UK.
⁴ Department of Health Sciences, University of Leicester, Leicester, UK.
⁵ Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, VA, USA.
⁶ Department of Surgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
⁷ Discovery Medicine, GlaxoSmithKline, Stevenage, UK.
⁸ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁹ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia.
¹⁰ Respiratory Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹¹ Department of Respiratory Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.
¹² Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
¹³ Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁴ Division of Pulmonary, Allergy and Critical Care Medicine, The University of Pittsburgh, Pittsburgh, PA, USA.
¹⁵ Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁶ Department of Internal Medicine, University of California Davis, Davis, CA, USA.
¹⁷ Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA.
¹⁸ National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton and Harefield Hospitals, London, UK; Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁹ National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton and Harefield Hospitals, London, UK.
²⁰ Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain.
²¹ National Heart and Lung Institute, Imperial College London, London, UK.
²² Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF.

Methods: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10^-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study.

Findings: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10^-12).

Interpretation: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF.

Funding: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Genome-Wide Association Study*
Humans
Idiopathic Pulmonary Fibrosis* / diagnosis
Lung
Lung Volume Measurements
Vital Capacity

Abstract

Publication types

MeSH terms

Grants and funding