title: 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.
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Sarig
authors.forename: Sivan
authors.initials: S
authors.lastname: Bercovici
authors.forename: Lilach
authors.initials: L
authors.lastname: Zoller
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldberg
authors.forename: Margarita
authors.initials: M
authors.lastname: Indelman
authors.forename: Sagi
authors.initials: S
authors.lastname: Nahum
authors.forename: Shirli
authors.initials: S
authors.lastname: Israeli
authors.forename: Nadav
authors.initials: N
authors.lastname: Sagiv
authors.forename: Helena
authors.initials: H
authors.lastname: Martinez de Morentin
authors.forename: Oren
authors.initials: O
authors.lastname: Katz
authors.forename: Sharon
authors.initials: S
authors.lastname: Baum
authors.forename: Aviv
authors.initials: A
authors.lastname: Barzilai
authors.forename: Henri
authors.initials: H
authors.lastname: Trau
authors.forename: Dedee F
authors.initials: DF
authors.lastname: Murrell
authors.forename: Reuven
authors.initials: R
authors.lastname: Bergman
authors.forename: Michael
authors.initials: M
authors.lastname: Hertl
authors.forename: Shai
authors.initials: S
authors.lastname: Rosenberg
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Karl
authors.initials: K
authors.lastname: Skorecki
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
authors.forename: Dan
authors.initials: D
authors.lastname: Geiger
authors.forename: Saharon
authors.initials: S
authors.lastname: Rosset
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D000368:Aged; D005260:Female; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010392:Pemphigus / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D012867:Skin / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; C497230:ST18 protein, human