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Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene
- Source :
- PLoS Genetics, PLoS Genetics, Vol 12, Iss 5, p e1006008 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
Abstract
- Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<br />Author Summary Pemphigus vulgaris is a life-threatening autoimmune skin blistering disease. A large body of evidence indicates that the propensity to develop this condition is in part genetically determined. Using a genome wide association approach, we recently identified pemphigus vulgaris-associated genetic variations in the vicinity of the ST18 gene. In the present study, we identify a risk variant residing within the ST18 promoter region which drives ST18 gene promoter activity in a p53/p63-dependent manner, which is in line with the fact that ST18 is up-regulated in the skin of PV patients. Using functional assays, we show that ST18 overexpression increases PV serum-induced expression of pro-inflammatory mediators, as well as augments PV serum-induced disruption of keratinocyte cell-cell adhesion, which are hallmarks of pemphigus pathogenesis. Our findings therefore support a direct role for ST18 in the pathogenesis of pemphigus vulgaris, and position ST18 as a new molecular target of potential interest for the treatment of disease. From a broader perspective, these observations underscore the importance of genetic variations affecting the susceptibility of target tissues to autoimmunity.
- Subjects :
- 0301 basic medicine
Keratinocytes
Male
Cancer Research
Physiology
Genome-wide association study
Disease
Pathogenesis
Pathology and Laboratory Medicine
Epithelium
030207 dermatology & venereal diseases
Database and Informatics Methods
0302 clinical medicine
Animal Cells
Risk Factors
Immune Physiology
Medicine and Health Sciences
Promoter Regions, Genetic
Genetics (clinical)
Skin
Genetics
Innate Immune System
High-Throughput Nucleotide Sequencing
Genomics
Genomic Databases
Pedigree
Cytokines
Female
Cellular Types
Anatomy
Sequence Analysis
Immunosuppressive Agents
Research Article
lcsh:QH426-470
Immunology
Biology
Research and Analysis Methods
Polymorphism, Single Nucleotide
Deep sequencing
03 medical and health sciences
Sequence Motif Analysis
medicine
Humans
Molecular Biology Techniques
Sequencing Techniques
Gene
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Secretion
Autoantibodies
Pemphigus vulgaris
Biology and Life Sciences
Computational Biology
Genetic Variation
Promoter
Epithelial Cells
Human Genetics
Cell Biology
Molecular Development
medicine.disease
Genome Analysis
Repressor Proteins
lcsh:Genetics
Pemphigus
030104 developmental biology
Biological Tissue
Biological Databases
Genetic Loci
Immune System
Cancer research
Physiological Processes
Developmental Biology
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 12
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....5cc5aeab2debfdbd8f812a483a9c941c