Identification of a susceptibility locus in <i>STAT4</i> for Behçet's disease in Han Chinese in a genome‐wide association study

Hou, Shengping; Yang, Zhenglin; Du, Liping; Jiang, Zhengxuan; Shu, Qinmeng; Chen, Yuanyuan; Li, Fuzhen; Zhou, Qingyun; Ohno, Shigeaki; Chen, Rui; Kijlstra, Aize; Rosenbaum, James T.; Yang, Peizeng

doi:10.1002/art.37708

Cited by 172 publications

(120 citation statements)

References 79 publications

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“…Besides our study, a recent six genome-wide association studies, [35][36][37][38][39][40] with the exception of the study by Fei et al, 35 have confirmed the association of BD with HLA-B51, and reported new susceptibility genes in the remaining part of the HLA class I region and several non-HLA genes for the disease. Two of them, conducted in Turkey 36 and Japan, 37 reported association between SNP of IL-10 and IL-23R/IL-12RB2 genes and BD.…”

supporting

confidence: 78%

Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions

Alpsoy

2016

The Journal of Dermatology

233

279

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supporting

confidence: 78%

Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions

Alpsoy

2016

The Journal of Dermatology

233

279

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“…While the association of rs6845297 with BD has not been previously tested, meta-analyses of our associations in NRG1 with those from previous reports in Turkish and Japanese [2,3] indicate that the susceptibility conferred by these variants is not restricted to the Iranian population and strengthen the role of NRG1 in BD susceptibility. The effect size of these NRG1 variants in BD susceptibility (ORs for the risk alleles of approximately 1.20) is much smaller than the effect of the wellestablished HLA-B51 allele (OR of approximately 3.50) [2,3] but is of the same magnitude as reported non-HLA allelic associations (ORs typically between 1.20 and 1.60) in genome-wide associations studies for BD [2,3,17,18]. Moreover, these three genetic markers have minor allele frequencies ranging from 0.122 to 0.473 in HapMap Caucasian (CEU) and Asian (CHB and JPT) populations, suggesting that these common variants may influence risk for BD in a substantial proportion of the population.…”

Section: Discussionmentioning

confidence: 79%

Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behçet's disease susceptibility

et al. 2013

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Behçet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes. The Epiregulin (EREG), Amphiregulin (AREG), and Neuregulin-1 (NRG1) genes of this pathway stand out as they are also among the top differentially expressed genes. Twelve haplotype tagging SNPs at the EREG-AREG locus and 15 SNPs in NRG1 found associated in at least one published BD genome-wide association study were tested for association with BD in a dataset of 976 Iranian patients and 839 controls. We found a novel association with BD for the rs6845297 SNP located downstream of EREG, and replicated three associations at NRG1 (rs4489285, rs383632, and rs1462891). Multifactor dimensionality reduction analysis indicated the existence of epistatic interactions between EREG and NRG1 variants. EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate BD susceptibility through main effects and gene-gene interactions. These association findings support a role for the EGF/ErbB signaling pathway in Electronic supplementary material The online version of this article

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“…The literature documenting this exaggerated innate immune response in BD is well reviewed by G€ ul [5]. In addition, there may well be a role for SNPs identified by genome-wide association studies (GWAS) as being associated with BD at a genome-wide association eight level (P < 5 3 10 28 ) [22,26,[65][66][67][68][69][70], reviewed by Takeuchi [71]. McGonagle shows how similar factors have been found in the pathogenesis of the other HLA-linked spondyloarthropathies [7].…”

Section: Misfolding Of Hla Proteins In Bd Pathogenesismentioning

confidence: 99%

Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

Giza

Koftori

Chen

et al. 2017

Clinical and Experimental Immunology

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Summary The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the ‘MHC-I-opathies’. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.

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Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome‐wide association study

Abstract: These findings strongly suggest that STAT4 is a novel locus underlying BD. We propose a model in which up-regulation of STAT4 expression and subsequent STAT4-driven production of inflammatory cytokines, such as IL-17, constitute a potential pathway leading to BD.

Cited by 172 publications

References 79 publications

Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions

Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions

Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behçet's disease susceptibility

Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

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