特发性肺纤维化的肺移植富集了端粒介导疾病的个体。
Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease.
机构信息
The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
出版信息
J Heart Lung Transplant. 2022 May;41(5):654-663. doi: 10.1016/j.healun.2021.11.008. Epub 2021 Nov 15.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients.
METHODS
Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review.
RESULTS
Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres.
CONCLUSIONS
There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.
背景
特发性肺纤维化（IPF）是北美肺移植最常见的适应证，端粒维持基因的变异是 IPF 最常见的可识别病因。我们推断，年轻的 IPF 患者更有可能接受肺移植，并且假设由于这些患者的发病更早且病情更严重，肺移植受者中会富集具有端粒介导疾病的个体。
方法
对接受肺移植或在特发性肺纤维化专科诊所接受评估但未接受肺移植的 IPF 患者进行了检查。通过对 426 名个体进行全基因组测序（WGS）和对 5 名个体进行靶向测序完成了基因评估。使用美国医学遗传学学院指南对先前与 IPF 相关的基因中的罕见变异进行分类。通过 TelSeq 软件从 WGS 数据测量端粒长度。通过病历回顾收集患者特征。
结果
在 431 名个体中，有 149 名因 IPF 行肺移植。移植与未移植个体的诊断中位年龄明显更年轻（分别为 60 岁和 70 岁，p<0.0001）。与未移植的个体相比，IPF 肺移植受者（IPF-LTR）发生与端粒相关的罕见变异的可能性是其两倍（分别为 24%和 12%，p=0.0013）。与未移植的 IPF 患者相比，IPF-LTR 的端粒更短（p=0.0028），超过 85%的个体的端粒低于年龄调整均值。在具有端粒维持基因罕见变异的 IPF-LTR 中，与没有这些变异的个体以及端粒较长的个体相比，移植后的生存和 CLAD 相似。
结论
在 IPF-LTR 中，端粒维持基因变异和端粒较短的情况更为常见。然而，在 IPF-LTR 中，生存和 CLAD 的移植结局不因基因变异或端粒长度而异。我们的发现支持这样一种观点，即不应将具有端粒介导疾病的个体排除在肺移植之外，并且应将研究重点放在针对端粒短介导疾病的个体的治疗方法上。
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