Population-Specific Association between a Polymorphic Variant in ST18, Encoding a Pro-Apoptotic Molecule, and Pemphigus Vulgaris

Abstract

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by anti-epithelial antibodies, leading to disruption of cell-cell adhesion. Although the disease is exceedingly rare worldwide, it is known to be relatively prevalent in Jewish populations. The low prevalence of the disease represents a significant obstacle to a genome-wide approach to the mapping of susceptibility genes. We reasoned that the study of a genetically homogeneous cohort characterized by a high prevalence of PV may help exposing associated signals while reducing spurious results due to population sub-structure. We performed a genome-wide association study using 300K single-nucleotide polymorphisms (SNPs) in a case-control study of 100 PV patients of Jewish descent and 397 matched control individuals, followed by replication of significantly associated SNPs in three additional cohorts of Jewish, Egyptian, and German origin. In addition to the major histocompatibility complex locus, a genomic segment on 8q11.23 that spans the ST18 gene was also found to be significantly associated with PV. This association was confirmed in the Jewish and Egyptian replication sets but not in the German sample, suggesting that ST18-associated variants may predispose to PV in a population-specific manner. ST18 regulates apoptosis and inflammation, two processes of direct relevance to the pathogenesis of PV. Further supporting the relevance of ST18 to PV, we found this gene to be overexpressed in the skin of PV patients as compared with healthy individuals.

The Genetics of Human Skin Disease

“…Several GWAS studies have been performed on at least 11 polygenic dermatology-related diseases within the last 6 yr (Petukhova et al 2010;Sarig et al 2012;Zhang 2012;Luo et al 2013 Sjögren's syndrome confirming previous findings from parametric linkage analysis and genome-wide scans as well as identifying new risk variants (Fig. 3).…”

Pemphigus

“…Three other alleles ( HLA-DRB1*03 , HLA-DRB1*07 and HLA-DRB1*15 ) had a lower prevalence in patients with pemphigus vulgaris 26 , whereas HLA-E*0103 , a non-classical class IB allele, and a non-HLA marker encoding suppression of tumorigenicity 18 protein (ST18; a molecule that regulates apoptosis and inflammation) have both been associated with pemphigus vulgaris 28,29 . However, the association between ST18 and pemphigus vulgaris found in Jewish and Egyptian patients was not confirmed in German patients, suggesting that ST18-associated variants may predispose to pemphigus vulgaris in a population-specific manner 29 . Moreover, a pemphigus vulgaris-associated functional risk variant residing within the ST18 promoter region may be linked to the secretion of key inflammatory molecules by keratinocytes after autoantibody binding (tumour necrosis factor (TNF), IL-1α and IL-6) 30 .…”

From Epidemiology and Genetics to Diagnostics, Outcome Measures, and Novel Treatments in Autoimmune Bullous Diseases

“…This effort can be achieved within the framework of the International Autoimmune Blistering Diseases Genetics Consortium. Following the first GWAS in pemphigus vulgaris patients (Sarig et al, 2012), the participants expect results from additional GWAS in BP, mucous membrane pemphigoid, and pemphigus within the next 2-3 years. The participants also agreed that novel technologies, such as next-generation sequencing, will be the driving force behind the progress in this field in the next years.…”

“…The results of the first genome-wide association study (GWAS) in pemphigus vulgaris patients were presented. The study, which was recently published in this journal, led to the identification of ST-18 as a susceptibility gene in pemphigus vulgaris (Sarig et al, 2012). In addition to GWAS, functional and metagenomic genetic studies are expected to provide further insights into AIBD pathogenesis.…”