TY - JOUR
T1 - Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis
T2 - a genome-wide association study
AU - CleanUP-IPF Investigators of the Pulmonary Trials Cooperative
AU - Allen, Richard J.
AU - Oldham, Justin M.
AU - Jenkins, David A.
AU - Leavy, Olivia C.
AU - Guillen-Guio, Beatriz
AU - Melbourne, Carl A.
AU - Ma, Shwu Fan
AU - Jou, Jonathan
AU - Kim, John S.
AU - Fahy, William A.
AU - Oballa, Eunice
AU - Hubbard, Richard B.
AU - Navaratnam, Vidya
AU - Braybrooke, Rebecca
AU - Saini, Gauri
AU - Roach, Katy M.
AU - Tobin, Martin D.
AU - Hirani, Nik
AU - Whyte, Moira K.B.
AU - Kaminski, Naftali
AU - Zhang, Yingze
AU - Martinez, Fernando J.
AU - Linderholm, Angela L.
AU - Adegunsoye, Ayodeji
AU - Strek, Mary E.
AU - Maher, Toby M.
AU - Molyneaux, Philip L.
AU - Flores, Carlos
AU - Noth, Imre
AU - Gisli Jenkins, R.
AU - Wain, Louise V.
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144533340&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(22)00251-X
DO - 10.1016/S2213-2600(22)00251-X
M3 - Article
C2 - 35985358
AN - SCOPUS:85144533340
SN - 2213-2600
VL - 11
SP - 65
EP - 73
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 1
ER -
