Table 7.
Descriptive and statistical characteristics of selected gene candidates in epidermal and dermal tissue
| Gene symbol | Description | FDR | Log2FC | Log2CPM | Notes/data related Justification |
|---|---|---|---|---|---|
| Epidermal candidates | |||||
| ADAMTS16 | ADAM Metallopeptidase With Thrombospondin Type 1 Motif 16 | N/A | N/A | N/A |
WGS data: Novel variant Denoted deleterious by PolyPhen2,PROVENA and SIFT scores. CADD score 33 Only variants graded as High and subcategorised as Level 1 for disease relevance and pathogenicity Known links to fibrosis |
| ADAMTSL1 | ADAMTS Like 1 | N/A | N/A | N/A |
WGS data only: Novel variant Denoted deleterious by PolyPhen2,PROVENA and SIFT scores. CADD score 30 Only variants graded as High and subcategorised as Level 1 for disease relevance and pathogenicity Known links to fibrosis |
| LAMA4 | Laminin subunit alpha 4 | 0.026 | − 1.26 | 2.21 |
RNA-seq data: Significant FDR, log2FC < -1 Known links to fibrosis in other organs Plausible involvement in epidermal-dermal interactions in pathogenic mechanisms |
| IFI27 | Interferon Alpha Inducible Protein 27 | 0.952 | 1.565 | 5.721 |
Only epidermal transcript with log2FC > 1.5 Epidermal GSEA, Hallmark gene set leading edge gene: IFNα signaling (NES = 1.924, FDR = 0.0011) IFNγ signaling (NES = 1.591, FDR = 0.014) Plausible epidermal early ‘damage’ signal, with links to downregulation of NR4A1 |
| TGF-β1 | Transforming Growth Factor Beta 1 | 0.990 | -0.036 | 5.362 |
Key initiator and mediator of fibrosis Epidermal expression never specifically investigated in morphoea Overall signaling (TGF-β signaling Hallmark set) strongly positively enriched via GSEA analysis (NES = 2.006, FDR = 0.001) |
| JUNB | JunB Proto-Oncogene, AP-1 Transcription Factor Subunit | 0.952 | 0.424 | 7.939 |
Relatively high log2CPM of 7.939 Epidermal GSEA, Hallmark gene set leading edge gene in TGF-β signaling Hallmark set (NES = 2.006, FDR = 0.001) |
| PAX3 | Paired box gene 3 | N/A | N/A | N/A |
Epidermal WGS: nonsynonymous protein coding deleterious SNV Links to epidermal upregulation of PAX8 as well as many other PAX, HOX, SOX and CBX genes in both epidermal and dermal datasets; many with links to fibrosis and SSc |
| Dermal candidates | |||||
| SFRP4 | Secreted Frizzled Related Protein 4 | < 0.001 | 3.277 | 5.582 |
Frizzled related protein with significant differential expression and log2FC > 3 Dermal GSEA, Hallmark gene set leading edge gene: Epithelial to mesenchymal transition (NES = 1.536, FDR = 0.125), highest ranked leading edge gene |
| SIX1 | SIX Homeobox 1 | 0.641 | 2.333 | 2.529 | Homeobox gene with the highest log2FC |
| WNT2 | Wnt Family Member 2 | 0.061 | 1.793 | 2.283 |
Only Wnt signaling with log2FC > 1.5 Differential expression approaching significance Dermal GSEA, Hallmark gene set leading edge gene: Notch signaling, top 20 positively enriched sets (NES = 0.980, FDR = 0.655), highest ranked leading edge gene PANTHER statistical enrichment test: Present within the significantly enriched Multicellular organism development gene set (PANTHER GO-Slim Biological Process), P = 0.007 |
| NOTCH4 | Notch Receptor 4 | 0.008 | 0.500 | 5.631 |
Only significantly differentially expressed NOTCH gene Relatively high log2CPM |
| NR4A1 | Nuclear Receptor Subfamily 4 Group A Member 1 | 0.003 | −0.63 | 4.81 |
Significant dermal downregulation Downregulated by IFI27 (see above) Endogenous regulator of TGF-β1 signaling and known involvement in fibrotic processes |
| CXCL9 | C-X-C Motif Chemokine Ligand 9 | < 0.001 | 2.71 | 3.88 |
Inflammatory IFN response related gene with significant and strong differential expression Dermal (and epidermal) GSEA, Hallmark gene set leading edge gene: Contribution to the leading edge gene profile for IFNγ signaling in both the dermis and epidermis Suggested as a biomarker in morphoea |
| CCL2 | C-C Motif Chemokine Ligand 2 | 0.034 | 0.7 | 4.34 |
Inflammatory IFN response related gene with significant differential expression Dermal (and epidermal) GSEA, Hallmark gene set leading edge gene: Contribution to the leading edge gene profile for IFNγ signaling in both the dermis and epidermis Over-expressed amongst morphoea patients included in the Milano et al. ‘intrinsic gene subset’ scleroderma study and has been isolated to dermal macrophages in morphoea |