Assassi Shervin, Wu Minghua, Tan Filemon K, Chang Jeffrey, Graham Tiffany A, Furst Daniel E, Khanna Dinesh, Charles Julio, Ferguson Emma C, Feghali-Bostwick Carol, Mayes Maureen D
University of Texas Health Science Center at, Houston.
Arthritis Rheum. 2013 Nov;65(11):2917-27. doi: 10.1002/art.38101.
We undertook this hypothesis-generating study to identify skin transcripts correlating with severity of interstitial lung disease (ILD) in systemic sclerosis (SSc).
Skin biopsy samples from 59 patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort or an open-label imatinib study (baseline visit) were examined by global gene expression analysis using Illumina HT-12 arrays. Skin transcripts correlating with concomitantly obtained forced vital capacity (FVC) values and the modified Rodnan skin thickness score (MRSS) were identified by quantitative trait analysis. Also, immunofluorescence staining for selected transcripts was performed in affected skin and lung tissue. Plasma levels of CCL2, soluble SELP, and soluble P-selectin glycoprotein ligand 1 (sPSGL-1) were examined in all patients enrolled in the GENISOS cohort (n = 266).
Eighty-two skin transcripts correlated significantly with FVC. This gene list distinguished patients with more severe ILD (FVC <70% predicted) in unsupervised hierarchical clustering analysis (P < 0.001). These genes included SELP, CCL2, and matrix metalloproteinase 3, which are involved in extravasation and adhesion of inflammatory cells. Among the FVC correlates, 8 genes (CCL2, HAPLN3, GPR4, ADCYAP1, WARS, CDC25B, PLP1, and STXBP6) also correlated with the MRSS. Immunofluorescence staining revealed that SELP and CCL2 were also overexpressed in affected skin and lung tissue from SSc patients compared to those from controls. Plasma levels of CCL2 and sPSGL-1 correlated with concomitantly obtained FVC values (r = -0.22, P = 0.001 and r = 0.17, P = 0.015, respectively). This relationship was independent of potential confounders (age, sex, ethnicity, smoking status, anti-topoisomerase I positivity, treatment with immunosuppressive agents, MRSS, disease type, and disease duration).
A limited number of skin transcripts including genes involved in extravasation and adhesion of inflammatory cells correlate with severity of ILD.
我们开展了这项生成假设的研究，以确定与系统性硬化症（SSc）中间质性肺病（ILD）严重程度相关的皮肤转录本。
对参与硬皮病结局研究中的遗传学与环境研究（GENISOS）队列或一项开放标签伊马替尼研究（基线访视）的59例患者的皮肤活检样本，使用Illumina HT - 12芯片通过全基因表达分析进行检测。通过数量性状分析确定与同时获得的用力肺活量（FVC）值和改良Rodnan皮肤厚度评分（MRSS）相关的皮肤转录本。此外，对选定转录本在受累皮肤和肺组织中进行免疫荧光染色。在GENISOS队列的所有患者（n = 266）中检测血浆CCL2、可溶性SELP和可溶性P - 选择素糖蛋白配体1（sPSGL - 1）水平。
82个皮肤转录本与FVC显著相关。在无监督层次聚类分析中，该基因列表区分出ILD更严重（FVC <预测值的70%）的患者（P < 0.001）。这些基因包括SELP、CCL2和基质金属蛋白酶3，它们参与炎症细胞的外渗和黏附。在与FVC相关的基因中，8个基因（CCL2、HAPLN3、GPR4、ADCYAP1、WARS、CDC25B、PLP1和STXBP6）也与MRSS相关。免疫荧光染色显示，与对照组相比，SSc患者受累皮肤和肺组织中SELP和CCL2也过表达。血浆CCL2和sPSGL - 1水平与同时获得的FVC值相关（r = -0.22，P = 0.001和r = 0.17，P = 0.015）。这种关系独立于潜在混杂因素（年龄、性别、种族、吸烟状态、抗拓扑异构酶I阳性、免疫抑制剂治疗、MRSS、疾病类型和病程）。
包括参与炎症细胞外渗和黏附的基因在内的有限数量的皮肤转录本与ILD严重程度相关。
