Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands.
Service de Pneumologie, Centre constitutif du centre de référence, des Maladies Pulmonaires Rares, DHU FIRE, Hôpital Bichat, APHP, INSERM, Unité 1152, LabEx Inflamex, Université Paris Diderot, Paris, France.
Curr Opin Pulm Med. 2018 May;24(3):269-280. doi: 10.1097/MCP.0000000000000475.
Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes.
Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause.
Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.
端粒相关基因的基因组突变已被认为是特发性肺纤维化（IPF）家族形式的病因。然而，越来越明显的是，端粒综合征和端粒缩短与各种类型的肺部疾病有关。此外，还发现端粒相关基因中的单核苷酸多态性（SNP）也是肺部疾病发展的危险因素。本综述重点介绍了端粒相关基因遗传变异与肺部表型相关的最新研究进展。
七个端粒相关基因的基因组突变可导致肺部疾病。这些突变相关的肺部表型范围从多种形式的肺纤维化到肺气肿和肺血管疾病。端粒相关突变占特发性间质性纤维化的 10%，家族性特发性肺纤维化的 25%，结缔组织疾病相关间质性肺疾病的 10%，慢性阻塞性肺疾病的 1%。也发现了混合疾病形式。此外，TERT、TERC、OBFC1 和 RTEL1 的 SNP 以及短端粒长度与多种肺部疾病有关。目前，端粒相关基因突变引起的肺部疾病的治疗主要基于疾病诊断，而不是潜在病因。
携带端粒相关基因突变和 SNP 的患者的肺部表型主要是肺纤维化，有时是肺气肿，很少是肺血管疾病。基因型-表型关系较弱，表明环境因素和患者的遗传背景在很大程度上决定了疾病表型。只要端粒相关基因的遗传变异在环境暴露、合并症或未知因素的触发下导致特定的肺部疾病表型，就会提出疾病模型。
