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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\n      \u003Ch2\u003ESummary\u003C\/h2\u003E\n      \u003Cp id=\u0022p-1\u0022\u003EBeh\u00e7et disease (BD) is a genetically complex condition that is characterized by recurrent inflammatory attacks that affect the orogenital mucosa, eyes, and skin. Genomewide association studies have linked the IL10 and IL23R-IL12RB2 loci to BD susceptibility [Remmers EF et al. \u003Cem\u003ENat Genet\u003C\/em\u003E 2010; Mizuki N et al. \u003Cem\u003ENat Genet\u003C\/em\u003E 2010].\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Evasculitis clinical trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n      \u003Cp id=\u0022p-2\u0022\u003EBeh\u00e7et disease (BD) is a genetically complex condition that is characterized by recurrent inflammatory attacks that affect the orogenital mucosa, eyes, and skin. Earlier genomewide association studies (GWAS) have linked the \u003Cem\u003EIL10\u003C\/em\u003E and \u003Cem\u003EIL23R-IL12RB2\u003C\/em\u003E loci to BD susceptibility [Remmers EF et al. \u003Cem\u003ENat Genet\u003C\/em\u003E 2010; Mizuki N et al. \u003Cem\u003ENat Genet\u003C\/em\u003E 2010]. Yohei Kirino, PhD, National Institutes of Health, Bethesda, Maryland, USA presented the findings of a GWAS analysis of imputed genotypes that are associated with BD.\u003C\/p\u003E\n      \u003Cp id=\u0022p-3\u0022\u003EAccording to Dr. Kirino, whole-genome imputation was used to identify additional BD susceptibility loci using 96 healthy Turkish controls who were genotyped on Illumina HumanOmni1M-Quad single-nucleotide polymorphism (SNP) chips as a reference. Imputation was conducted using MACH v1.0.15, providing 814,474 SNPs for analysis in 1215 BD cases and 1278 healthy controls. Sequenom iPLEX assays were used to validate the imputation results and to fine map the associated region. Two independent replication sets were genotyped for the most significant SNP.\u003C\/p\u003E\n      \u003Cp id=\u0022p-4\u0022\u003EA p-value cutoff of 1\u00d710\u003Csup\u003E5\u003C\/sup\u003E identified 114 non-HLA gene SNPs that were suggestive of association with BD. One imputed SNP, rs7616215 on chromosome 3, located approximately 38 kb from the 3\u2032 UTR of the chemokine receptor-1 gene (\u003Cem\u003ECCR1\u003C\/em\u003E) (OR, 0.71; p=1.9\u00d710\u003Csup\u003E\u22128\u003C\/sup\u003E), exceeded genomewide significance (p\u0026lt;5\u00d710\u003Csup\u003E\u22128\u003C\/sup\u003E). Fine mapping of the \u003Cem\u003ECCR1\/CCR3\u003C\/em\u003E locus confirmed the imputation results for rs7616215 and identified 2 additional SNPs in strong linkage disequilibrium with rs7616215. They also exceeded genomewide significance.\u003C\/p\u003E\n      \u003Cp id=\u0022p-5\u0022\u003EThe association of rs7616215 was replicated using additional Turkish and Japanese BD cases and controls in a meta-analysis of 2195 cases and 2187 controls (OR= 0.73; 95% CI, 0.66 to 0.81; p=1.8\u00d710\u003Csup\u003E\u221210\u003C\/sup\u003E).\u003C\/p\u003E\n      \u003Cp id=\u0022p-6\u0022\u003ECCR1 belongs to the family of CC-motif chemokine receptors. It is expressed on neutrophils, monocytes, and T lymphocytes and binds several chemokine ligands, including CCL5\/RANTES, CCL3\/MIP-1\u03b1, and CCL4\/MIP-1\u03b2. Serum levels of \u003Cem\u003ECCRI\u003C\/em\u003E ligands, the chemokines MIP-\u03b1 and RANTES, are increased in BD [Kim SK et al. \u003Cem\u003EScan J Rhematol\u003C\/em\u003E 2005; Ozer HT et al. \u003Cem\u003ERheumatol Int\u003C\/em\u003E 2005].\u003C\/p\u003E\n      \u003Cp id=\u0022p-7\u0022\u003EENCODE data suggest that the CCRI variant could affect transcription of CCR1\/CCR3 and that rs7616215 resides in a putative regulatory genomic domain. Analysis of \u003Cem\u003ECCR1\u003C\/em\u003E transcripts from the HapMap of European, Chinese, and Japanese subjects shows that the protective minor allele (C) correlates with significantly increased \u003Cem\u003ECCR1\u003C\/em\u003E expression (p\u0026lt;0.03). In addition, \u003Cem\u003ESTAT4\u003C\/em\u003E expression is increased in cells with the BD risk allele. \u003Cem\u003ESTAT4\u003C\/em\u003E is specifically activated by IL-12 and is a critical signaling mediator for the generation of IFN-\u03b3-producing Th1 T cells.\u003C\/p\u003E\n      \u003Cp id=\u0022p-8\u0022\u003EIn summary, imputation identified two novel loci, \u003Cem\u003ECCR1\/CCR3\u003C\/em\u003E and \u003Cem\u003ESTAT4\u003C\/em\u003E, that were associated with BD. \u003Cem\u003ECCR1\u003C\/em\u003E expression and leukocyte chemotaxis are higher in individuals with the protective allele. \u003Cem\u003ESTAT4\u003C\/em\u003E expression is higher in individuals with the risk allele. These results implicate leukocyte cell migration and Th1 T cells in the pathogenesis of BD.\u003C\/p\u003E\n      \u003Cp id=\u0022p-9\u0022\u003ETo date, HLA-B51 has been the most strongly associated known genetic factor in BD [de Menthon M et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2009]. This study\u0027s identification of \u003Cem\u003ECCR1\u003C\/em\u003E and \u003Cem\u003ESTAT4\u003C\/em\u003E as novel gene loci in BD has potential implications in the regulation of inflammatory responses in the context of the disease. Its findings suggest novel therapeutic targets for BD.\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/11\/13\/17.2.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmw81\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}