Targeted resequencing implicates the familial Mediterranean fever gene
            <i>MEFV</i>
            and the toll-like receptor 4 gene
            <i>TLR4</i>
            in Behçet disease

Kirino, Yohei; Zhou, Qing; Ishigatsubo, Yoshiaki; Mizuki, Nobuhisa; Tuğal-Tutkun, İlknur; Seyahi, Emire; Özyazgan, Yılmaz; Uğurlu, Serdal; Erer, Burak; Abacı, Neslihan; Ustek, Duran; Meguro, Akira; Ueda, Atsushi; Takeno, Mitsuhiro; Inoko, Hidetoshi; Ombrello, Michael J.; Satorius, Colleen; Maskeri, Baishali; Mullikin, James C.; Sun, Hongwei; Gutierrez-Cruz, Gustavo; Kim, Yoonhee; Wilson, Alexander F.; Kastner, Daniel L.; Gül, Ahmet; Remmers, Elaine F.

doi:10.1073/pnas.1306352110

Cited by 137 publications

(117 citation statements)

References 29 publications

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“…Although the strongest risk factor for BD remains HLA-B*51, which encodes what usually is considered an adaptive immune molecule, several recent genetic studies have clearly linked innate immune mechanisms to BD risk, supporting an autoinflammatory contribution to its pathogenesis (6,7). Our data bring additional insight to this discussion by offering a plausible mechanism through which MHC-I could act to confer risk of BD through the regulation of both innate NK cells and adaptive CTLs.…”

Section: Discussionmentioning

confidence: 56%

“…The predominant BD susceptibility locus is the MHC on chromosome 6 (2, 3), which contains the strongest known risk factor for BD, the MHC class I (MHC-I) allele HLA-B*51 (2)(3)(4)(5). Several recent studies have expanded the list of genes or loci implicated in the pathophysiology of BD, which now includes HLA-B, IL10, IL23R, HLA-A, CCR1, STAT4, endoplasmic reticulum amino peptidase 1 (ERAP1), the killer lectinlike receptor cluster on chromosome 12, and, most recently, TLR4 and MEFV (2,3,6,7). Although these genetic studies of BD have provided new clues and insights into the pathogenesis of BD, none has provided a thorough accounting of the individual risk factors within the MHC.…”

mentioning

confidence: 99%

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Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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124

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The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behçet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10 −8 ). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-Ikiller immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.HLA imputation | autoinflammation | antigen presentation | killer immunoglobulin-like receptors | natural killer cells

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Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 99%

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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124

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“…As this gene has a role in innate immunity, nonsynonymous variants identified by deep exonic resequencing of TNFRSF1A gene has been recently evaluated for BD association. 40 The association is shown to be significant 40 in the C-a test, the adaptive sum test, and the step-up test. Shahneh et al 39 also emphasized possible roles of IL6 and TGF-b during the differentiation of Th17 cells from naive T cells.…”

Section: No Of Common Snps In Commonly Associated Genes Commonly Assmentioning

confidence: 93%

“…[53][54][55] As part of this pathway, low-frequency and rare variants in the FN3, fibronectin tenth type III domain of IL23R gene were detected by targeted resequencing of TR and JP samples. 40 As shown in Table 2, IL2RB gene, which has the same FN3 domain, is targeted by the SNPs in both TR and JP populations. Considering the fact that the elucidation of the JAK/STAT pathway has provided many insights into disease mechanisms and has become the basis for new pharmacologic agents, here we would like to emphasize once again the importance of the pathway-oriented approach.…”

Section: Focal Adhesionmentioning

confidence: 99%

Identification of possible pathogenic pathways in Behçet’s disease using genome-wide association study data from two different populations

et al. 2014

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Behc¸et's disease (BD) is a multi-system inflammatory disorder of unknown etiology. Two recent genome-wide association studies (GWASs) of BD confirmed a strong association with the MHC class I region and identified two non-HLA common genetic variations. In complex diseases, multiple factors may target different sets of genes in the same pathway and thus may cause the same disease phenotype. We therefore hypothesized that identification of disease-associated pathways is critical to elucidate mechanisms underlying BD, and those pathways may be conserved within and across populations. To identify the disease-associated pathways, we developed a novel methodology that combines nominally significant evidence of genetic association with current knowledge of biochemical pathways, protein-protein interaction networks, and functional information of selected SNPs. Using this methodology, we searched for the disease-related pathways in two BD GWASs in Turkish and Japanese case-control groups. We found that 6 of the top 10 identified pathways in both populations were overlapping, even though there were few significantly conserved SNPs/genes within and between populations. The probability of random occurrence of such an event was 2.24E À39. These shared pathways were focal adhesion, MAPK signaling, TGF-b signaling, ECM-receptor interaction, complement and coagulation cascades, and proteasome pathways. Even though each individual has a unique combination of factors involved in their disease development, the targeted pathways are expected to be mostly the same. Hence, the identification of shared pathways between the Turkish and the Japanese patients using GWAS data may help further elucidate the inflammatory mechanisms in BD pathogenesis.

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“…The revelation of GWAS unfolded associations with genome-wide significance (P < 5 × 10 Targeted next-generation sequencing revealed the additional involvement of rare non-synonymous variants in toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domaincontaining protein 2 (NOD2), and the Mediterranean Fever Gene (MEFV) [37]. Recently, Ognenovski et al used whole exome sequencing in BD of European descent for the first time and identified and replicated two novel putative protein-damaging genetic variants within LIMK2 and NEIL1, which may influence cytoskeletal regulation and DNA repair [38].…”

Section: Non-mhc I Susceptibility Genesmentioning

confidence: 99%

Etiology, Immunopathogenesis and Biomarkers in Behçet’s disease

Adeeb¹,

Khan²,

Stack³

et al. 2017

Behcet's Disease

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Behçet's disease (BD) is a type of vasculitis with many distinctive clinical manifestations and multifactorial immunopathogenesis. The cause of BD remains unknown, but it has been postulated that in a genetically predisposed or susceptible population, exogenous agents trigger the dysregulation of both autoinflammatory and autoimmune responses resulting in multisystem vasculitis. There are robust ongoing efforts across the globe to elucidate and identify signature markers to improve and assist in rapid diagnosis of the disease and to tailor the best therapy accordingly. While association of human leukocyte antigen (HLA)-B * 51 (B * 51:01 subtype) allele is well recognized as the strongest genetic susceptibility gene so far among genetically predisposed BD patients, further investigations using the latest technology have led to the identification of several novel single nucleotide polymorphisms (SNPs) and other associated genes involved in the pathogenesis. There are several "established" cytokines known to be involved in the pathogenesis of BD, which have been further implicated in the genome-wide association studies (GWAS)-based cytokine/receptor gene loci studies, as well as numerous "novel" cytokines, which are currently being studied and identified. This chapter offers insights into current knowledge and thoughts regarding the future of biomarkers in BD.

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Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease

Cited by 137 publications

References 29 publications

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Identification of possible pathogenic pathways in Behçet’s disease using genome-wide association study data from two different populations

Etiology, Immunopathogenesis and Biomarkers in Behçet’s disease

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