Abstract
Purpose: To build a microRNA and gene signature of severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Methods: MicroRNA expression profiles were downloaded from miRNA expression profile of patients’ skin suffering from TEN using an array comprising of 372 miRNAs; download site: www.jacionline.org. The patient samples were eight TEN, ten SJS patients and twenty-two healthy individuals. A total of 192 microRNAs were found with unique expression patterns (overexpressed) in contrast with healthy skin controls and patients. Thereafter, the following databases were used for downstream analysis: geneMANIA, DIANA-miRPath version 3, DIANA-TarBase version 7.0, Ingenuity Pathway Analysis (IPA) as well as DAVID, STRING and GENECODIS online tools. Results: Granulysin (GNLY) geneMANIA database search yielded 21 interacting genes that were 64.6 % in physical interaction, 17 % in co-expression pattern. miRBD potential microRNAs that target the 21 genes were 79 miRs. Eighteen miRs overlap between the overexpressed miRs from SJS/TEN samples and the miRs targeting the 21 genes. Moreover, Ingenuity pathway analysis IPA revealed that the microRNAs were involved in inflammation. Conclusion: Analysis of differential microRNA expressions reveals two significant DE miRs that target Granulysin (483-5p/miR-28-5p). MiR-GNLY loop interactions in hypersensitivity reactions may function as biomarkers for SCAR including SJS and TEN. Keywords: Severe cutaneous adverse drug reactions (SCAR) Steven-Johnson Syndrome, Toxic epidermal necrolysis, Granulysin, Biomarkers, MicroRNA signature
Highlights
The clinical appearances of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN range from mild severe cutaneous adverse drug reactions (SCAR), both are rare but seldom fatal
MicroRNA expression profile were downloaded from the inclusive miRNA expression profile of patients skin suffering from TEN using an array comprising of 372 miRNAs; Ichihara et al article's Online Repository at www.jacionline.org [13]
1-DIANA-miRPath 70 pathway results for the microRNA. This search yielded more than 70 significant pathways; we chose the top ten according to p Value result and number of genes targeted by the miR list loaded to DIANA-miRPath tool
Summary
The clinical appearances of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN range from mild severe cutaneous adverse drug reactions (SCAR), both are rare but seldom fatal. SCAR are among the most significant serious skin conditions amid cutaneous drug-provoked hypersensitivity adverse conditions [3]. SJS and TEN rely on immune mediators in their hypersensitivity reactions that involve the cutaneous tissues and layers [4]. Mortality still occurs in over 5 % of hypersensitivity adverse patients with SJS and greater than 30 % of the same patients [5]. MicroRNAs are imposed as new regulators in adverse cutaneous reactions [8]. T-cell lymphocyte association with SJS and TEN was recently observed to be linked with skin reactions, in addition to the recently reported Granulysin and natural killer cells inhibitory receptors [9]. Granulysin acts as the substantial player and responsible for the dispersed keratinocyte death [10] and it has a role in cytotoxic T lymphocyte conditions [11]
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