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

Autor:	Allen RJ; Department of Health Sciences, University of Leicester, Leicester, UK. Electronic address: rja34@leicester.ac.uk., Oldham JM; Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA., Jenkins DA; Division of Informatics, Imaging & Data Sciences, University of Manchester, Manchester, UK., Leavy OC; Department of Health Sciences, University of Leicester, Leicester, UK., Guillen-Guio B; Department of Health Sciences, University of Leicester, Leicester, UK., Melbourne CA; Department of Health Sciences, University of Leicester, Leicester, UK., Ma SF; Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, VA, USA., Jou J; Department of Surgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA., Kim JS; Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, VA, USA., Fahy WA; Discovery Medicine, GlaxoSmithKline, Stevenage, UK., Oballa E; Discovery Medicine, GlaxoSmithKline, Stevenage, UK., Hubbard RB; 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., Navaratnam V; 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., Braybrooke R; 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., Saini G; Respiratory Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK., Roach KM; Department of Respiratory Sciences, University of Leicester, Glenfield Hospital, Leicester, UK., Tobin MD; Department of Health Sciences, University of Leicester, Leicester, UK., Hirani N; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Whyte MKB; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Kaminski N; Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA., Zhang Y; Division of Pulmonary, Allergy and Critical Care Medicine, The University of Pittsburgh, Pittsburgh, PA, USA., Martinez FJ; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA., Linderholm AL; Department of Internal Medicine, University of California Davis, Davis, CA, USA., Adegunsoye A; Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA., Strek ME; Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA., Maher TM; 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., Molyneaux PL; National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton and Harefield Hospitals, London, UK., Flores C; 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., Noth I; Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, VA, USA., Gisli Jenkins R; National Heart and Lung Institute, Imperial College London, London, UK., Wain LV; Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
Jazyk:	angličtina
Zdroj:	The Lancet. Respiratory medicine [Lancet Respir Med] 2023 Jan; Vol. 11 (1), pp. 65-73. Date of Electronic Publication: 2022 Aug 16.
DOI:	10.1016/S2213-2600(22)00251-X
Abstrakt:	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. Competing Interests: Declaration of interests LVW reports research funding from GlaxoSmithKline and Orion Pharma, and consultancy for Galapagos, outside of the submitted work. JMO reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio, and Lupin Pharmaceuticals, outside of the submitted work. RGJ is a trustee of Action for Pulmonary Fibrosis and reports personal fees from AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daewoong, Galapagos, Galecto, GlaxoSmithKline, Heptares, NuMedii, PatientMPower, Pliant, Promedior, Redx, Resolution Therapeutics, Roche, Veracyte, and Vicore, outside of the submitted work. AA reports personal fees from Boehringer Ingelheim and Genentech, outside of the submitted work. NK served as a consultant to Biogen, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, TheraVance, Indalo, LifeMax, Three Lake Partners, Optikira, AstraZeneca, Rohbar, Veracyte, Augmanity, Gilead, Chiesi, Arrowhead, CSL-Behring, Galapagos, and Thyron over the past 3 years; reports Equity in Pliant and Thyron; reports being a scientific founder of Thyron; grants from Veracyte, Boehringer Ingelheim, Bristol Myers Squibb, and the Three Lakes Foundation; non-financial support from MiRagen and AstraZeneca; and has intellectual property on novel biomarkers and therapeutics in idiopathic pulmonary fibrosis licensed to Biotech. MDT reports grants or contracts from research collaborations with GlaxoSmithKline and Orion Pharma. RBH reports grants or contracts from Galapagos for serving on a trial adjudication outcome committee for an IPF trial, from AstraZeneca for serving on a COVID-19 vaccine safety committee, and from Boehringer Ingelheim for an IPF service provision consultation. WAF and EO are employees of GlaxoSmithKline. All other authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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