An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis
An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis
复制标题
DOI：
10.1164/rccm.201610-2088oc
复制
发表时间：
2017-07-01
影响因子：
24.7
通讯作者：
Goldstein, David B.
中科院分区：
文献类型：
--
作者：
Petrovski, Slave;Todd, Jamie L.;Goldstein, David B.
基本原理：特发性肺纤维化（IPF）是一种日益被认识的、常常是致命的、病因不明的肺部疾病。目的：本研究的目的是使用全外显子组测序来提高对肺纤维化遗传结构的理解。方法：我们进行了一项病例对照全外显子组崩溃分析，包括262名根据美国胸科学会/美国胸科学会临床分类为IPF的肺纤维化无关个体。欧洲呼吸学会/日本呼吸学会/拉丁美洲胸科协会指南（81.3%）、继发于自身免疫性疾病的普通型间质性肺炎（11.5%）或纤维化非特异性间质性肺炎（7.2%）。大多数（87%）病例受试者没有肺纤维化家族史。测量和主要结果：我们使用来自262名肺纤维化病例受试者和4，141名对照受试者的全外显子组序列数据，搜索了18，668个蛋白编码基因，以寻找过量的罕见有害遗传变异。对照受试者来自一组欧洲血统的个体。比较18,668个蛋白质编码基因的遗传变异，我们发现在整个研究范围内，TERT、RTEL 1和PARN的合格变异体显著富集（P < 4.5 x 10（-7））。一种模型鉴定了涉及TERT和RTEL 1的极端、有害、非同义变体，一种模型专门鉴定了涉及RTEL 1和PARN的功能丧失变体。对186例散发性IPF病例受试者进行的亚组分析证实，TERT、RTEL 1和PARN是整个研究范围内散发性IPF的显著促成因素。总体而言，11.3%的散发性IPF病例受试者携带这三种基因之一的合格变异，而对照受试者中观察到的携带率为0.3%（比值比，47.7; 95%可信区间，21.5-111.6; P = 5.5x10（-22））。我们鉴定了TERT、RTEL 1和PARN--三个以前与家族性肺纤维化有关的端粒相关基因--作为散发性IPF的重要贡献者。这些结果支持端粒功能障碍参与IPF发病机制的观点。
Rationale: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.Objectives: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis.Methods: 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.Measurements and Main Results: 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 x 10(-7)) 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 = 5.5x10(-22)).Conclusions: 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.