title: Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis.
abstract: OBJECTIVE
  We undertook this hypothesis-generating study to identify skin transcripts correlating with severity of interstitial lung disease (ILD) in systemic sclerosis (SSc).
  
  
  METHODS
  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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  A limited number of skin transcripts including genes involved in extravasation and adhesion of inflammatory cells correlate with severity of ILD.
authors.affiliation: University of Texas Health Science Center at, Houston.
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chang
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Graham
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.forename: Julio
authors.initials: J
authors.lastname: Charles
authors.forename: Emma C
authors.initials: EC
authors.lastname: Ferguson
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D001706:Biopsy; D017675:CREST Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D017563:Lung Diseases, Interstitial / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index; D012879:Skin Physiological Phenomena / Q000235:genetics*; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate
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