Meta-Analysis

. 2023 Jan;11(1):65-73.

doi: 10.1016/S2213-2600(22)00251-X. Epub 2022 Aug 16.

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

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.

PMID: 35985358
PMCID: PMC10077113
DOI: 10.1016/S2213-2600(22)00251-X

Meta-Analysis

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

Richard J Allen et al. Lancet Respir Med. 2023 Jan.

. 2023 Jan;11(1):65-73.

doi: 10.1016/S2213-2600(22)00251-X. Epub 2022 Aug 16.

Authors

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.

PMID: 35985358
PMCID: PMC10077113
DOI: 10.1016/S2213-2600(22)00251-X

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Figure 1:. Manhattan plots for longitudinal FVC (A) and DLCO (B) genome-wide meta-analyses**
Each point represents a variant, with chromosomal position on the x axis and –log10(p value) on the y axis. The red horizontal line shows the genome-wide significance threshold of p=5 × 10⁻⁸. DLCO=diffusing capacity of the lung for carbon monoxide. FVC=forced vital capacity. *PKN2*-AS1=protein kinase N2 gene in introns of the antisense RNA.

**Figure 2:. Forest plot for rs115982800**
Effect size estimates for each study are shown with squares and the bars show the 95% CI. The size of the square is relative to the weight given to each study in the meta-analysis (which is based on the inverse of the standard error). Meta-analysis results are shown by diamonds. Effect estimates to the left of the vertical line suggest that allele A is associated with a more rapid decline in lung function. CleanUP-IPF=Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis study. FVC=forced vital capacity. GWAS=genome-wide association study. USS=US, UK, and Spain.

**Figure 3:. Region plot for the locus significantly associated with FVC decline**
Each point represents a variant, with chromosomal position on the x axis and −log₁₀(p value) on the y axis. The dashed horizontal line shows the genome-wide significance threshold of p=5 × 10⁻⁸. Variants are coloured by linkage disequilibrium with the sentinel variant (rs115982800) depicted as a diamond. Light blue lines show the recombination rate and gene positions are shown below the x axis. The plot was created using LocusZoom. FVC=forced vital capacity.

See this image and copyright information in PMC

Comment in

Genetic associations and lung function in IPF: unexpected answers, persistent questions.
Mathai SK. Mathai SK. Lancet Respir Med. 2023 Jan;11(1):5-6. doi: 10.1016/S2213-2600(22)00270-3. Epub 2022 Aug 16. Lancet Respir Med. 2023. PMID: 35985356 No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous