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

被引:39
|
作者
Vodo, Dan [1 ,2 ]
Sarig, Ofer [1 ]
Geller, Shamir [1 ]
Ben-Asher, Edna [3 ]
Olender, Tsviya [3 ]
Bochner, Ron [1 ]
Goldberg, Ilan [1 ]
Nosgorodsky, Judith [1 ]
Alkelai, Anna [3 ]
Tatarskyy, Pavel [3 ]
Peled, Alon [1 ,2 ]
Baum, Sharon [4 ]
Barzilai, Aviv [4 ]
Ibrahim, Saleh M. [5 ]
Zillikens, Detlef [6 ]
Lancet, Doron [3 ]
Sprecher, Eli [1 ,2 ]
机构
[1] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Dermatol, IL-69978 Tel Aviv, Israel
[2] Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel
[3] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel
[4] Sheba Med Ctr, Dept Dermatol, Tel Hashomer, Israel
[5] Med Univ Lubeck, Inst Expt Dermatol, D-23538 Lubeck, Germany
[6] Med Univ Lubeck, Dept Dermatol, D-23538 Lubeck, Germany
来源
PLOS GENETICS | 2016年 / 12卷 / 05期
基金
以色列科学基金会;
关键词
NECROSIS-FACTOR-ALPHA; BINDING-SITE; TNF-ALPHA; IN-VITRO; P53; P63; DNA; ACANTHOLYSIS; EXPRESSION; DISSOCIATION;
D O I
10.1371/journal.pgen.1006008
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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< 0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.
引用
收藏
页数:13
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