Short telomeres are a risk factor for idiopathic pulmonary fibrosis
Short telomeres are a risk factor for idiopathic pulmonary fibrosis
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DOI：
10.1073/pnas.0804280105
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发表时间：
2008-09-02
影响因子：
11.1
通讯作者：
Armanios, Mary Y.
中科院分区：
文献类型：
--
作者：
Alder, Jonathan K.;Chen, Julian J. -L.;Armanios, Mary Y.
特发性间质性肺炎 (IIP) 病程呈进行性且常常致命，其神秘的病因使有效治疗方法变得复杂。特发性肺纤维化 (IPF) 是最常见的 IIP，并且与 IIP 一样，其发病率随着年龄的增长和肺部不明原因的疤痕而增加。短端粒限制了肺部的组织更新能力，而端粒酶成分、hTERT 和 hTR 的种系突变是 IPF 家族子集遗传的基础。为了检验短端粒导致散发性 IIP 疾病风险的假设，我们招募了没有家族史的患者，并检查了白细胞和肺泡细胞中的端粒长度。为了筛选突变，我们对 hTERT 和 hTR 进行了测序。我们还回顾了病例的端粒综合征特征。 IIP 患者的白细胞端粒比年龄匹配的对照组短（P < 0.0001）。在一个子集（10%）中，IIP 患者的端粒长度低于其年龄的第一个百分位。与突变家族病例相似，IPF 患者肺泡上皮细胞端粒较短（P < 0.0001）。尽管端粒酶突变很罕见，仅在 100 名患者中就有 1 人检测到，但我们发现了一群患有 IPF 和隐源性肝硬化（端粒综合征的另一个特征）的个体 (3%)。因此，短端粒是 IIP 的一个特征，并且可能在其与年龄相关的发病中发挥作用。隐源性肝硬化与 IPF 的聚集表明，我们发现的端粒缩短会产生后果，并可能导致临床上出现的肺和肝脏特发性进行性器官衰竭。
Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.