Abstract
BackgroundMarfan 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.Methodology/Principal FindingsHere 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.Conclusion/SignificanceIn conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.
Highlights
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with a systemic involvement
MFS is caused by mutations in the fibrillin-1 gene (FBN1, MIM 134797) coding for the fibillin-1 protein, which is an abundant component of the extracellular matrix throughout all organsystems [2,3]
The variable and unpredictable clinical course of the disease hampers clinical management and counseling of these patients. In this transcriptome wide gene expression study, we investigated the role of Transforming Growth Factor-b (TGF-b) and inflammation related genes within a group of MFS patients, to elucidate if these pathways are correlated to MFS severity or specific MFS clinical features
Summary
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with a systemic involvement. Other organ systems like lungs, dura and in tegmentum are often affected It has an incidence of approximately 1 in 5,000 and is probably the most common monogenetic connective tissue disorder [1]. Due to a defect or deficient fibrillin-1, enhanced release and activation of TGF-b occurs in the extracellular matrix. Both Smad-dependent and noncanonical (ERK dependent) TGF-b signaling contribute to the development of aortic root aneurysm in mouse model of MFS [5,6]. Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. The contribution of tissue inflammation is not addressed so far
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