Systems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms
Figure 3
Information graph and consensus clusters for the MPH cohorts.
(A) The information graph of the MPH cohorts is highly modular (cf. S2 Fig.), indicating approximate conservation of gene expression modules across datasets. The information graph is tripartite by construction, so a triangle in the graph necessarily connects modules across all three datasets. The triangles form communities of mutual edge sharing. Colored nodes and edges highlight four of these communities. The purple community contains modules that are up-regulated in the inflammatory subset (cf. panel B). The red community contains modules that are up-regulated in the fibroproliferative subset (cf. panel B). The cyan community contains modules that are enriched for keratinocyte-specific processes. The orange community contains modules that are enriched for fatty acid metabolism genes. The remaining communities (22 in all and not colored to avoid cluttering the display) are enriched primarily for housekeeping processes and are neither skin- nor disease-specific (see Table 3). (B) Modules from the communities were tested for their enrichment in the subsets. Each row corresponds to a triangle in the information graph and each column corresponds to a dataset. The black lines separate communities, e.g. all of the rows in the block marked “1” correspond triangles in community 1. The cells are colored according to whether the module was significantly differentially expressed in a subset with dark colors representing up-regulation and light colors representing down-regulation (Bonferroni-corrected Wilcoxon rank sum p-value p<0.05). We assessed statistical significance of modules within each dataset for each of the three diffuse SSc intrinsic subsets, as well as all SSc vs. healthy controls (Purple- Inflammatory, Red- Proliferation, Green- Normal-like, Blue- All SSc). Note the inflammatory up community (*) and the fibroproliferative up community (**). Note also that community 2 is significantly highly expressed in the inflammatory subset and lowly expressed in the proliferative subset in Milano only. Likewise, community 9 appears to be expressed at low levels in the inflammatory subset in Milano, but none of the other data sets.