University of Texas Southwestern Medical Center, Dallas, TX, USA.
University of California San Francisco, San Francisco, CA, USA.
Lancet Respir Med. 2014 Jul;2(7):557-65. doi: 10.1016/S2213-2600(14)70124-9. Epub 2014 Jun 16.
Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.
In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).
370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p<0.0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1.33 [SD 0.25]) were similar to the 221 patients with other interstitial lung disease diagnoses (1.46 [0.24]) after adjusting for age, sex, and ethnicity (p=0.47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0.22 [95% CI 0.08-0.63]; p=0.0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0.73 [0.16-3.41]; p=0.69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0.11 [0.03-0.39], p=0.00066; San Francisco cohort, HR 0.25 [0.07-0.87], p=0.029).
Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis.
US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.
特发性肺纤维化患者的一部分存在端粒较短，但它们的临床意义尚不清楚。我们的目的是研究具有不同血液白细胞端粒长度的患者是否具有不同的总生存期。
在这项观察性队列研究中，我们从达拉斯（TX）（主要队列）以及芝加哥（IL）和旧金山（CA）招募了患有间质性肺病的患者。我们从达拉斯的无关健康对照者中获得了基因组 DNA 样本，并且还招募了患者的配偶作为独立对照组。在初始入组评估时，从外周血中提取基因组 DNA 样本，测量端粒长度。达拉斯队列的主要终点是无移植存活（即死亡或肺移植时间）。在两个独立的特发性肺纤维化队列（芝加哥和旧金山）中验证了发现结果。
2003 年 6 月 17 日至 2011 年 8 月 25 日，在达拉斯队列中纳入了 370 名患者。与 195 名健康对照者相比，特发性肺纤维化患者的端粒较短（平均年龄调整后的对数转化端粒与单拷贝基因的比值为-0.16[标准差 0.23] vs 0.00[0.18]；p<0.0001）；然而，调整年龄、性别和种族后，达拉斯特发性肺纤维化患者的端粒长度（1.33[标准差 0.25]）与其他 221 名间质性肺疾病诊断患者的端粒长度相似（1.46[0.24]）（p=0.47）。端粒长度与特发性肺纤维化患者的无移植存活时间独立相关（HR 0.22[95%CI 0.08-0.63]；p=0.0048），但与特发性肺纤维化以外的其他间质性肺疾病患者无关（HR 0.73[0.16-3.41]；p=0.69）。特发性肺纤维化患者端粒长度与生存之间的关联独立于年龄、性别、用力肺活量或一氧化碳弥散量，并且在两个独立的特发性肺纤维化复制队列中得到了复制（芝加哥队列，HR 0.11[0.03-0.39]，p=0.00066；旧金山队列，HR 0.25[0.07-0.87]，p=0.029）。
较短的白细胞端粒长度与特发性肺纤维化患者的生存率较差相关。需要进一步研究来确定端粒长度的临床相关阈值，以及该生物标志物如何影响特发性肺纤维化患者的风险分层。
美国国家心肺血液研究所、国家转化医学科学中心、Harroun 家庭基金会和 Nina Ireland 肺病计划。
