Petrovski Slavé, Todd Jamie L, Durheim Michael T, Wang Quanli, Chien Jason W, Kelly Fran L, Frankel Courtney, Mebane Caroline M, Ren Zhong, Bridgers Joshua, Urban Thomas J, Malone Colin D, Finlen Copeland Ashley, Brinkley Christie, Allen Andrew S, O'Riordan Thomas, McHutchison John G, Palmer Scott M, Goldstein David B
1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
2 Department of Medicine, Austin Health and Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
Am J Respir Crit Care Med. 2017 Jul 1;196(1):82-93. doi: 10.1164/rccm.201610-2088OC.
Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.
The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis.
We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis.
We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10).
We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.
特发性肺纤维化（IPF）是一种病因不明、日益受到关注且往往致命的肺部疾病。
本研究旨在通过全外显子组测序来加深对肺纤维化遗传结构的理解。
我们进行了一项病例对照全外显子组归约分析，纳入了262名无亲缘关系的肺纤维化患者，这些患者根据美国胸科学会/欧洲呼吸学会/日本呼吸学会/拉丁美洲胸科学会指南被临床分类为IPF（81.3%）、自身免疫性疾病继发的普通间质性肺炎（11.5%）或纤维化非特异性间质性肺炎（7.2%）。大多数（87%）病例受试者无肺纤维化家族史。
我们利用262例肺纤维化病例受试者和4141例来自欧洲血统个体的对照受试者的全外显子组序列数据，在18668个蛋白质编码基因中搜索罕见有害遗传变异的过量情况。比较18668个蛋白质编码基因的遗传变异，我们发现TERT、RTEL1和PARN基因中符合条件的变异在全研究范围内具有显著的病例富集（P < 4.5 × (10^{-7})）。一个筛选超罕见、有害、非同义变异的模型涉及TERT和RTEL1，一个专门筛选功能丧失变异的模型涉及RTEL1和PARN。对186例散发性IPF病例受试者的亚分析证实，TERT、RTEL1和PARN是散发性IPF在全研究范围内的显著贡献因素。总体而言，11.3%的散发性IPF病例受试者在这三个基因中的一个携带符合条件的变异，而对照受试者中的携带率为0.3%（优势比，47.7；95%置信区间，21.5 - 111.6；P = 5.5 × (10^{-14})）。
我们确定了TERT、RTEL1和PARN这三个先前与家族性肺纤维化有关的端粒相关基因，它们是散发性IPF的重要贡献因素。这些结果支持端粒功能障碍参与IPF发病机制的观点。
