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Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: A genome-wide association study
Hubbard, Richard B. Navaratnam, Vidya Braybrooke, Rebecca Saini, Gauri
Hubbard, Richard B.
Navaratnam, Vidya
Braybrooke, Rebecca
Saini, Gauri
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-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 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p-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. 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.
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Date
2023
Type
Article
Subject
Idiopathic pulmonary fibrosis, Lung, Disease progression
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Citation
Allen, R.J., Oldham, J.M., Jenkins, D.A., Leavy, O.C., Guillen-Guio, B., Melbourne, C.A., Ma, S., Jou, J., Kim, J.S., Fahy, W.A., Oballa, E., Hubbard, R.B., Navaratnam, V., Braybrooke, R., Saini, G., Roach, K.M., Tobin, M.D., Hirani, N., Whyte, M.K.B., Kaminski, N., Zhang, Y., Martinez, F.J., Linderholm, A.L., Adegunsoye, A., Strek, M.E., Maher, T.M., Molyneaux, P.L., Flores, C., Noth, I., Gisli Jenkins, R. and Wain, L.V. (2023) 'Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: A genome-wide association study', The Lancet Respiratory Medicine, 11(1), pp. 65-73. doi: 10.1016/S2213-2600(22)00251-X https://doi.org/10.1016/s2213-2600(22)00251-x.