Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/40576
Title: Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study
Authors: 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
First Published: 20-Oct-2017
Publisher: Elsevier
Citation: The Lancet Respiratory Medicine, 2017, 5(11), pp. 869-880
Abstract: Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. Methods We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls. Findings 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18–1·37], p=1·32 × 10−9) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56–3·26], p=1·12 × 10−66) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35–1·54], p=7·81 × 10−28). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51). Interpretation AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF.
DOI Link: 10.1016/S2213-2600(17)30387-9
ISSN: 2213-2600
eISSN: 2213-2619
Links: http://www.sciencedirect.com/science/article/pii/S2213260017303879?via%3Dihub
http://hdl.handle.net/2381/40576
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Health Sciences

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