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

Allen, Richard J; Porte, Joanne; Braybrooke, Rebecca; Flores, Carlos; Fingerlin, Tasha E; Oldham, Justin M.; Guillen-Guio, Beatriz; Ma, Shwu-Fan; Okamoto, Tsukasa; 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; 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; Marshall, Richard P; Oballa, Eunice; Bossé, Yohan; Nickle, David C; Sin, Don D; Timens, Wim; Shrine, Nick; Sayers, Ian; Hall, Ian P.; Noth, Imre; Schwartz, David A.; Tobin, Martin D.; Wain, Louise V.; Jenkins, R. Gisli

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).

Citation

Allen, R. J., Porte, J., Braybrooke, R., Flores, C., Fingerlin, T. E., Oldham, J. M., Guillen-Guio, B., Ma, S.-F., Okamoto, T., John, A. E., Obeidat, M., Yang, I. V., Henry, A., Hubbard, R. B., Navaratnam, V., Saini, G., Thompson, N., Booth, H. L., Hart, S. P., Hill, M. R., …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

• Journal Article Type: Article
• Acceptance Date: Sep 28, 2017
• Online Publication Date: Oct 20, 2017
• Publication Date: Nov 1, 2017
• Deposit Date: Sep 28, 2017
• Publicly Available Date: Oct 20, 2017
• Journal: The Lancet respiratory medicine
• Print ISSN: 2213-2600
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 11
• Pages: 869-880
• DOI: https://doi.org/10.1016/s2213-2600%2817%2930387-9
• Keywords: Idiopathic pulmonary fibrosis
• Public URL: https://hull-repository.worktribe.com/output/455279
• 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.
• Contract Date: Sep 28, 2017