Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene

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
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.