@article { , title = {Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study}, 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).}, doi = {10.1016/s2213-2600(17)30387-9}, eissn = {2213-2619}, issn = {2213-2600}, issue = {11}, journal = {The Lancet respiratory medicine}, pages = {869-880}, publicationstatus = {Published}, publisher = {Elsevier}, url = {https://hull-repository.worktribe.com/output/455279}, volume = {5}, keyword = {Health and Health Inequalities, Idiopathic pulmonary fibrosis}, year = {2017}, author = {Allen, Richard J and Porte, Joanne and Braybrooke, Rebecca and Flores, Carlos and Fingerlin, Tasha E and Oldham, Justin M. and Guillen-Guio, Beatriz and Ma, Shwu-Fan and Okamoto, Tsukasa and John, Alison E and Obeidat, Ma'en and Yang, Ivana V. and Henry, Amanda and Hubbard, Richard B and Navaratnam, Vidya and Saini, Gauri and Thompson, Norma and Booth, Helen L and Hart, Simon P and Hill, Mike R and Hirani, Nik and Maher, Toby M and McAnulty, Robin J and Millar, Ann B. and Molyneaux, Philip L and Parfrey, Helen and Rassl, Doris M and Whyte, Moira K.B. and Fahy, William A and Marshall, Richard P and Oballa, Eunice and Bossé, Yohan and Nickle, David C and Sin, Don D and Timens, Wim and Shrine, Nick and Sayers, Ian and Hall, Ian P. and Noth, Imre and Schwartz, David A. and Tobin, Martin D. and Wain, Louise V. and Jenkins, R. Gisli} }