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Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study
The Lancet Respiratory Medicine ( IF 38.7 ) Pub Date : 2017-10-20 , DOI: 10.1016/s2213-2600(17)30387-9
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

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.

Funding

UK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.



中文翻译:

欧洲血统人群中与特发性肺纤维化易感性相关的遗传变异:全基因组关联研究

背景

特发性肺纤维化(IPF)是一种慢性进行性肺部疾病,死亡率高,病因不确定且治疗选择不多。研究发现与IPF的发展相关的重大遗传风险;然而,遗传风险因素促进IPF的机制仍不清楚。我们旨在鉴定与IPF易感性相关的遗传变异,并使用基因和蛋白质表达分析提供机制的见解。

方法

我们采用了两个阶段的方法:从英国的9个不同中心招募的欧洲血统IPF患者进行全基因组关联研究,并从UK Biobank(第1阶段)中选择适合年龄,性别和吸烟状况的对照。以及对来自IPF患者和对照的独立数据集中相关遗传变异的随访,这些数据来自芝加哥联合体和科罗拉多联合体的两个独立的美国样本(第2阶段)。我们调查了大转录组和基因组数据资源中新信号对基因表达的影响,并使用来自IPF和对照患者的肺组织样本检查了表达。

发现

选择602例IPF患者和3366例对照进行1期治疗。对于2期,选择2158例IPF患者和5195例对照。我们在A激酶锚定蛋白13(AKAP13 ; rs62025270,比值比[OR] 1·27 [95%CI 1·18-1·37],p = 1)附近发现了与IPF敏感性相关的新型全基因组显着信号。·32×10 -9)和先前证实的信号,包括粘蛋白5B(MUC5B; rs35705950或OR 2·89 [2·56-3·26],p = 1·12×10 -66)和去铁素(DSP ; rs2076295,或1·44 [1·35-1·54],p = 7·81×10 -28)。对于rs62025270,与IPF易感性增加相关的等位基因A也与AKAP13的表达增加相关接受过肺切除手术的患者肺组织中的mRNA(n = 1111)。我们显示,AKAP13在IPF患者的肺泡上皮和淋巴滤泡中表达,并且IPAP患者(n = 46)的肺组织中AKAP13 mRNA的表达是对照组(n = 46)的1·42倍。 = 51)。

解释

AKAP13是调节RhoA激活的Rho鸟嘌呤核苷酸交换因子,已知它参与纤维化信号通路。AKAP13作为IPF的易感基因的鉴定增加了成功靶向IPF患者的RhoA途径抑制剂的前景。

资金

英国医学研究委员会,美国国立卫生研究院国立心脏,肺和血液研究所,西班牙国家创新研究中心,西班牙国立卫生研究院和英国肺病基金会。

更新日期:2017-10-20
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