Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.
Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.
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DOI：
10.1016/s2213-2600(17)30387-9
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Jenkins RG
中科院分区：
文献类型：
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作者：
Allen RJ;Porte J;Braybrooke R;Flores C;Fingerlin TE;Oldham JM;Guillen-Guio B;Ma SF;Okamoto T;John AE;Obeidat M;Yang IV;Henry A;Hubbard RB;Navaratnam V;Saini G;Thompson N;Booth HL;Hart SP;Hill MR;Hirani N;Maher TM;McAnulty RJ;Millar AB;Molyneaux PL;Parfrey H;Rassl DM;Whyte MKB;Fahy WA;Marshall RP;Oballa E;Bossé Y;Nickle DC;Sin DD;Timens W;Shrine N;Sayers I;Hall IP;Noth I;Schwartz DA;Tobin MD;Wain LV;Jenkins RG
特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，死亡率高，病因不明，治疗选择少。研究已经确定了与IPF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。我们的目的是确定与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见解。我们使用了两阶段方法：在从英国9个不同中心招募的欧洲血统IPF患者和从英国生物样本库（第1阶段）中选择的年龄、性别和吸烟状态匹配的对照中进行全基因组关联研究;以及随访来自芝加哥联盟和科罗拉多联盟的两个独立美国样本的IPF患者和对照的独立数据集中的相关遗传变异（阶段2）。我们研究了新信号对大型转录组和基因组数据资源中基因表达的影响，并使用IPF患者和对照组的肺组织样本检测了表达。第1阶段选择了602例IPF患者和3366例对照。对于第2阶段，选择了2158例IPF患者和5195例对照。我们在A激酶锚定蛋白13附近发现了一个与IPF易感性相关的新的全基因组显著信号（AKAP 13; rs62025270，比值比[OR] 1·27 [95% CI 1·18-1·37]，p=1·32 × 10−9），并证实了先前报道的信号，包括粘蛋白5 B（MUC 5 B; rs35705950，OR 2·89 [2·56-3·26]，p=1·12 × 10−66）和桥斑蛋白（DSP; rs 2076295，OR 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也与肺切除术患者肺组织中AKAP 13 mRNA表达增加相关（n=1111）。我们发现，AKAP 13在IPF患者的肺泡上皮和淋巴滤泡中表达，并且IPF患者（n=46）的肺组织中AKAP 13 mRNA表达是对照组（n=51）肺组织中的1.42倍。AKAP 13是一种Rho鸟嘌呤核苷酸交换因子，调节RhoA的活化，已知其参与促纤维化信号传导途径。AKAP 13作为IPF易感基因的鉴定增加了在IPF患者中成功靶向RhoA通路抑制剂的前景。英国医学研究理事会、美国国立卫生研究院国家心脏、肺和血液研究所、西班牙加那利群岛研究、创新和信息社会组织、英国国家健康研究所和英国肺脏基金会。
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. 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. 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). 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. 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.