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一种基于核小体的新型模型，用于识别和诊断 SSc-ILD。

A new nucleosomic-based model to identify and diagnose SSc-ILD.

机构信息

Pneumology Department, CHU Liège, Domaine Universitaire du Sart-Tilman, B35, B4000, Liège, Belgium.

Rheumatology Department, CHU Liège, Domaine Universitaire du Sart-Tilman, B35, B4000, Liège, Belgium.

出版信息

Clin Epigenetics. 2020 Aug 17;12(1):124. doi: 10.1186/s13148-020-00915-4.

DOI:10.1186/s13148-020-00915-4

PMID:32807242

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7430109/

Abstract

BACKGROUND

Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the evolution of the lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease. Nucleosomes are stable DNA/protein complexes that are shed into the blood stream making them ideal candidates for biomarkers.

METHODS

We studied circulating cell-free nucleosomes (cf-nucleosomes) in SSc patients, 31 with ILD (SSc-ILD) and 67 without ILD. We analyzed plasma levels for cf-nucleosomes and investigated whether global circulating nucleosome levels in association with or without other biomarkers of interest for systemic sclerosis or lung fibrosis (e.g., serum growth factors: IGFBP-1 and the MMP enzyme: MMP-9), could be suitable potential biomarkers for the correct identification of SSc-ILD disease.

RESULTS

We found that H3.1 nucleosome levels were significantly higher in patients with SSc-ILD compared SSc patients without ILD (p < 0.05) and levels of MMP-9 were significantly increased in patients with SSc-ILD compared to SSc patients without ILD (p < 0.05). Conversely, IGFBP-1 was significantly reduced in patients with SSc-ILD compared to SSc without ILD (p < 0.001). The combination of cf-nucleosomes H3.1 coupled to MMP-9 and IGFBP-1 increased the sensitivity for the differential detection of SSc-ILD. High levels of accuracy were reached with this combined model: its performances are strong with 68.4% of positive predictive value and 77.2% of negative predictive value for 90% of specificity. With our model, we identified a significant negative correlation with FVC % pred (r = -0.22) and TLC % pred (r = -0.31). The value of our model at T1 (baseline) has a predictive power over the Rodnan score at T2 (after 6-18 months), showed by a significant linear regression with R = 19% (p = 0.013). We identified in the sole group of SSc-ILD patients a significant linear regression with a R = 54.4% with the variation of DLCO between T1 and T2 (p < 0.05).

CONCLUSION

In our study, we identified a new blood-based model with nucleosomic biomarker in order to diagnose SSc-ILD in a SSc cohort. This model is correlated with TLC and FVC at baseline and predictive of the skin evolution and the DLCO. Further longitudinal exploration studies should be performed in order to evaluate the potential of such diagnostic and predictive model.

摘要

背景

系统性硬化症（SSc）是一种罕见的结缔组织疾病，与快速进展的间质性肺病（SSc-ILD）相关，导致其死亡率升高。非常需要与肺病进展相关的特定生物标志物。我们旨在确定 SSc-ILD 的特定生物标志物，以预测疾病的进展。核小体是稳定的 DNA/蛋白质复合物，会释放到血液中，使其成为生物标志物的理想候选物。

方法

我们研究了 SSc 患者的循环无细胞核小体（cf-nucleosomes），其中 31 例有间质性肺病（SSc-ILD），67 例无间质性肺病。我们分析了 cf-nucleosomes 的血浆水平，并研究了是否可以将与系统性硬化症或肺纤维化相关的其他感兴趣的生物标志物（例如，血清生长因子：IGFBP-1 和 MMP 酶：MMP-9）的整体循环核小体水平作为合适的潜在生物标志物，以正确识别 SSc-ILD 疾病。

结果

我们发现，与无间质性肺病的 SSc 患者相比，有间质性肺病的 SSc 患者的 H3.1 核小体水平显着升高（p<0.05），并且有间质性肺病的 SSc 患者的 MMP-9 水平显着升高（p<0.05）。相反，与无间质性肺病的 SSc 患者相比，IGFBP-1 在有间质性肺病的 SSc 患者中显着降低（p<0.001）。cf-nucleosomes H3.1 与 MMP-9 和 IGFBP-1 的组合增加了对 SSc-ILD 差异检测的敏感性。该组合模型达到了较高的准确性水平：其性能非常强，阳性预测值为 68.4%，阴性预测值为 77.2%，特异性为 90%。使用我们的模型，我们发现与 FVC%pred（r=-0.22）和 TLC%pred（r=-0.31）之间存在显着的负相关。在 T1（基线）时，该模型的值对 T2（6-18 个月后）的 Rodnan 评分具有预测能力，这通过 R=19%（p=0.013）的显着线性回归显示出来。我们在单纯的 SSc-ILD 患者组中发现，DLCO 在 T1 和 T2 之间的变化与 R=54.4%（p<0.05）之间存在显着的线性回归关系。