Pemphigus Vulgaris Is Associated with the Transporter Associated with Antigen Processing (TAP) System

Slomov, Elena; Loewenthal, Ron; Korostishevsky, Michael; Goldberg, Ilan; Brenner, Sarah; Gazit, Ephraim

doi:10.1016/j.humimm.2005.11.004

Cited by 17 publications

(15 citation statements)

References 49 publications

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“…This observation could be consistent with previous studies showing evidence of multiple independent associations in the MHC region (Shams et al, 2009). The TAP2 gene, which is essential for class I antigen processing, was inducible by IFN-g and had been identified in a previous association study (Slomov et al, 2005). The strong association of HLA class II with PV implies the involvement of CD4 þ T cells, which play a critical role in the induction and regulation of antibody production, in the pathogenesis .…”

Section: Discussionmentioning

confidence: 91%

“…To detect additional susceptibility genes and optimally use the GWAS data sets for PV, we conducted gene-and pathwaybased analyses using versatile gene-based association study (VEGAS), in which the SNPs in the GWAS analysis were mapped to approximately 15,711 genes. Four genes were significantly associated with the disease (i.e., they exceeded a Bonferroni-corrected threshold of P < 3.2 Â 10 e6 ); three of these genes (HLA-DQA1 [Shams et al, 2009], IL6 [Pereira et al, 2004], and TAP2 [Slomov et al, 2005]) had been previously implicated in a published genetic study of pemphigus (see Supplementary Table S1 online). The HLA-DRB1 (P ¼ 1.13 Â 10 e4 ) and UBASH3B (P ¼ 3.96 Â 10 e2 ) genes (also known as STS1) reached a borderline significant level in this analysis, whereas the ST18 gene (Sarig et al, 2012) (P ¼ 2.25 Â 10 e1 ) showed no significant association.…”

Section: Results Of Gene-based and Gene Set Enrichment Analysismentioning

confidence: 99%

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Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population

Gao

Zhu

Zhang

et al. 2018

Journal of Investigative Dermatology

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To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.

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Section: Discussionmentioning

confidence: 91%

Section: Results Of Gene-based and Gene Set Enrichment Analysismentioning

confidence: 99%

Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population

Gao

Zhu

Zhang

et al. 2018

Journal of Investigative Dermatology

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“…Pemphigus vulgaris (PV), as the most common clinical variant, plays a significant role in increasing the prevalence among distinct ethnic groups such as Iranians, Indians and Jews . In addition, a number of studies have reported a high prevalence of specific HLA and other non‐HLA genes alleles in these ethnic groups . Like ethnic heterogeneity, some other factors such as familial occurrence and the presence of circulating PV IgG autoantibodies in healthy first‐degree relatives of PV patients suggested a genetic predisposition for PV.…”

Section: Introductionmentioning

confidence: 99%

The association betweenST18 gene polymorphism and severe pemphigus disease among Iranian population

Etesami

Hassan

Ghandi

et al. 2018

Experimental Dermatology

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Recently, ST18 polymorphism has played a role in increasing the risk of pemphigus among some populations such as Egyptian and Jewish. In addition, a variant within the ST18 promoter gene was shown to induce ST18 upregulation and cytokine secretion leading to keratinocyte susceptibility to anti-desmoglein antibodies. Thus, the present study aimed to assess the ST18 single nucleotide polymorphisms (SNP) relationship with pemphigus, disease severity and family history among Iranian population. A total of 111 pemphigus patients and 201 healthy controls were genotyped for three ST18 SNPs rs2304365, rs10504140 and rs4074067 by using TETRA-ARMS PCR method. The results indicated that risk allele A in rs2304365 was significantly higher in pemphigus patients, compared with the amount in the control group (OR = 2.43 CI = 1.49-3.975, P < 0.001). Thus, A allele represents a risk factor for pemphigus. Further, the patients carrying the risk allele had a more severe disease and a higher age of disease onset while no relationship was observed between the number of relapses and positive family history of pemphigus with the risk allele. Finally, dominant model was regarded as the strongest inheritance model for the associated risk. The present study confirmed the relationship between ST18 gene with pemphigus disease, a more severe disease, and a higher age of disease onset.

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“…A number of candidate gene-driven case-control studies conducted in various populations have revealed associations between pemphigus and HLA class I and II regions, non-HLA genes at the same loci, as well as genes encoding relevant autoantigens (Miyagawa et al, 2002;Gazit and Loewenthal, 2004;Slomov et al, 2005;Tron et al, 2005;Capon et al, 2006;Brick et al, 2007;Javor et al, 2009;Shams et al, 2009;Tunca et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Sarig

Bercovici

Zoller

et al. 2012

Journal of Investigative Dermatology

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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.

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Pemphigus Vulgaris Is Associated with the Transporter Associated with Antigen Processing (TAP) System

Cited by 17 publications

References 49 publications

Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population

Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population

The association betweenST18 gene polymorphism and severe pemphigus disease among Iranian population

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

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