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Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study

Allen, Richard J; John, Alison E; Obeidat, Ma'en; Yang, Ivana V.; Henry, Amanda; Hubbard, Richard B; Navaratnam, Vidya; Saini, Gauri; Thompson, Norma; Booth, Helen L; Hart, Simon P; Porte, Joanne; Hill, Mike R; Hirani, Nik; Maher, Toby M; McAnulty, Robin J; Millar, Ann B.; Molyneaux, Philip L; Parfrey, Helen; Rassl, Doris M; Whyte, Moira K.B.; Fahy, William A; Braybrooke, Rebecca; Marshall, Richard P; Oballa, Eunice; Bossé, Yohan; Nickle, David C; Sin, Don D; Timens, Wim; Shrine, Nick; Sayers, Ian; Hall, Ian P.; Noth, Imre; Flores, Carlos; Schwartz, David A.; Tobin, Martin D.; Wain, Louise V.; Jenkins, R. Gisli; Fingerlin, Tasha E; Oldham, Justin M.; Guillen-Guio, Beatriz; Ma, Shwu-Fan; Okamoto, Tsukasa

Authors

Richard J Allen

Joanne Porte

Rebecca Braybrooke

Carlos Flores

Tasha E Fingerlin

Justin M. Oldham

Beatriz Guillen-Guio

Shwu-Fan Ma

Tsukasa Okamoto

Alison E John

Ma'en Obeidat

Ivana V. Yang

Amanda Henry

Richard B Hubbard

Vidya Navaratnam

Gauri Saini

Norma Thompson

Helen L Booth

Simon P Hart

Mike R Hill

Nik Hirani

Toby M Maher

Robin J McAnulty

Ann B. Millar

Philip L Molyneaux

Helen Parfrey

Doris M Rassl

Moira K.B. Whyte

William A Fahy

Richard P Marshall

Eunice Oballa

Yohan Bossé

David C Nickle

Don D Sin

Wim Timens

Nick Shrine

Ian Sayers

Ian P. Hall

Imre Noth

David A. Schwartz

Martin D. Tobin

Louise V. Wain

R. Gisli Jenkins

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause and limited treatment options. Recent studies have identified a significant genetic risk associated with the development of IPF, however mechanisms by which genetic risk factors promote IPF remain unclear. Methods: We used a two-stage approach comprising a genome-wide association study in 602 UK IPF cases with 3,366 controls (stage 1) and follow-up of associated variants in independent datasets totalling 2,158 IPF cases and 5,195 controls (stage 2). We investigated the effect of novel signals on gene expression levels in large transcriptomic and genomic data resources, and examined expression levels using lung tissue samples from IPF cases and controls. Findings: We identified a novel genome-wide significant signal of association with IPF susceptibility near AKAP13 (rs62025270, OR=1.27 [1.18, 1.37], p=1.32×10−9) and replicated previously reported signals, including in MUC5B and DSP. For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue (n=1,111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF and there was a 1.42 fold higher expression of AKAP13 mRNA in IPF lung tissue (n=47) compared with controls (n=51). Interpretation: AKAP13 is a RhoGEF regulating activation of RhoA, which is known to be involved in pro-fibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with this devastating disease. Funding: Genotyping of stage 1 samples was funded by MRC Strategic Award to I.P.H., M.D.T., L.V.W. and Professor David Strachan (MC_PC_12010). MRC grants: G0901226 (R.G.J.); G1000861, NHLBI grants: R01 HL097163, P01 HL092870. B.G.G. was supported by fellowship from ACIISI (TESIS2015010057). T.M. is supported by NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017).

Journal Article Type Article
Publication Date Nov 1, 2017
Journal The Lancet respiratory medicine
Print ISSN 2213-2600
Electronic ISSN 2213-2619
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 5
Issue 11
Pages 869-880
Institution Citation Allen, R. J., Porte, J., Braybrooke, R., Flores, C., Fingerlin, T. E., Oldham, J. M., …Jenkins, R. . G. (2017). Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study. The lancet. Respiratory medicine, 5(11), 869-880. https://doi.org/10.1016/s2213-2600%2817%2930387-9
DOI https://doi.org/10.1016/s2213-2600%2817%2930387-9
Keywords Idiopathic pulmonary fibrosis
Publisher URL http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30387-9/fulltext
Additional Information This article is maintained by: Elsevier; Article Title: Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study; Journal Title: The Lancet Respiratory Medicine; CrossRef DOI link to publisher maintained version: http://dx.doi.org/10.1016/S2213-2600(17)30387-9; CrossRef DOI link to the associated document: http://dx.doi.org/10.1016/S2213-2600(17)30394-6; Content Type: article; Copyright: © 2017 The Author(s). Published by Elsevier Ltd.

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Copyright Statement
© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.




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