title: Inflammation aggravates disease severity in Marfan syndrome patients.
abstract: BACKGROUND
  Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.
  
  
  RESULTS
  Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.
  
  
  CONCLUSIONS
  In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Teodora
authors.initials: T
authors.lastname: Radonic
authors.forename: Piet
authors.initials: P
authors.lastname: de Witte
authors.forename: Maarten
authors.initials: M
authors.lastname: Groenink
authors.forename: Vivian
authors.initials: V
authors.lastname: de Waard
authors.forename: Rene
authors.initials: R
authors.lastname: Lutter
authors.forename: Marco
authors.initials: M
authors.lastname: van Eijk
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.forename: Marlies
authors.initials: M
authors.lastname: Kempers
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Scholte
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hilhorst-Hofstee
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Baars
authors.forename: Barbara J M
authors.initials: BJ
authors.lastname: Mulder
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
mesh_terms: D000293:Adolescent; D000328:Adult; D001011:Aorta / Q000473:pathology; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood; D004108:Dilatation, Pathologic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000235:genetics*; D008297:Male; D008382:Marfan Syndrome / Q000097:blood / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012720:Severity of Illness Index; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000097:blood; D055815:Young Adult
chemical_list: D016207:Cytokines; D016212:Transforming Growth Factor beta