TY - JOUR
T1 - Dissecting the psoriasis transcriptome
T2 - Inflammatory- and cytokine-driven gene expression in lesions from 163 patients
AU - Swindell, William R.
AU - Johnston, Andrew
AU - Voorhees, John J.
AU - Elder, James T.
AU - Gudjonsson, Johann E.
N1 - Funding Information:
This work was supported by NIH K08 AR060802 (JEG), R01 AR054966 (JTE), the Babcock Endowment Fund, Dermatology Foundation, American Skin Association, and the A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (JEG). Dr. Swindell is funded by the Carson Family Research Scholar Award in Psoriasis (American Skin Association). Dr. Johnston is funded by the American Skin Association and the Babcock Endowment Fund. Dr. Elder is supported by the Ann Arbor VA Hospital.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - Background: Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample.Results: We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders.Conclusions: Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.
AB - Background: Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample.Results: We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders.Conclusions: Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.
KW - AP-1
KW - Etanercept
KW - IL-17
KW - IL-20
KW - Inflammation
KW - Keratinocyte
KW - Microarray
KW - T-cell
KW - TNF
KW - Transcription factor
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U2 - 10.1186/1471-2164-14-527
DO - 10.1186/1471-2164-14-527
M3 - Article
C2 - 23915137
AN - SCOPUS:84880891082
SN - 1471-2164
VL - 14
JO - BMC Genomics
JF - BMC Genomics
IS - 1
M1 - 527
ER -