{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:14:26Z","timestamp":1789186466968,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2012,11,28]],"date-time":"2012-11-28T00:00:00Z","timestamp":1354060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify susceptibility loci for Beh\u00e7et's disease (BD) and elucidate their functional role.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A genome\u2010wide association study (GWAS) and functional studies were conducted. A total of 149 patients and 951 controls were enrolled in the initial GWAS, and 554 patients and 1,159 controls were enrolled in the replication study. Real\u2010time polymerase chain reaction, luciferase reporter assay, and enzyme\u2010linked immunosorbent assay were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our GWAS and replication studies identified a susceptibility locus around <jats:italic>STAT4<\/jats:italic> (single\u2010nucleotide polymorphisms [SNPs] rs7574070, rs7572482, and rs897200; <jats:italic>P<\/jats:italic> = 3.36 \u00d7 10<jats:sup>\u22127<\/jats:sup> to 6.20 \u00d7 10<jats:sup>\u22129<\/jats:sup>). Increased expression of <jats:italic>STAT4<\/jats:italic> was observed in individuals carrying the rs897200 risk genotype AA. Consistent with the idea that <jats:italic>STAT4<\/jats:italic> regulates the production of interleukin\u201017 (IL\u201017) and interferon\u2010\u03b3, <jats:italic>IL17<\/jats:italic> messenger RNA and protein levels were increased in individuals carrying the rs897200 risk genotype AA. Interestingly, the risk allele A of rs897200 creates a putative transcription factor binding site. To test whether it directly affects <jats:italic>STAT4<\/jats:italic> transcription, an in vitro luciferase reporter gene assay was performed. Higher transcription activity was observed in individuals carrying the risk allele A, suggesting that rs897200 is likely to directly affect <jats:italic>STAT4<\/jats:italic> expression. Additionally, 2 SNPs, rs7574070 and rs7572482, which are tightly linked with rs897200, were <jats:italic>cis<\/jats:italic>\u2010expression quantitative trait loci (eQTL) SNPs, suggesting that SNP rs897200 is an eQTL SNP. Most importantly, the clinical disease severity score was higher in individuals with the rs897200 risk genotype AA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings strongly suggest that <jats:italic>STAT4<\/jats:italic> is a novel locus underlying BD. We propose a model in which up\u2010regulation of <jats:italic>STAT4<\/jats:italic> expression and subsequent <jats:italic>STAT4<\/jats:italic>\u2010driven production of inflammatory cytokines, such as IL\u201017, constitute a potential pathway leading to BD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.37708","type":"journal-article","created":{"date-parts":[[2012,9,22]],"date-time":"2012-09-22T16:27:14Z","timestamp":1348331234000},"page":"4104-4113","source":"Crossref","is-referenced-by-count":168,"title":["Identification of a susceptibility locus in <i>STAT4<\/i> for Beh\u00e7et's disease in Han Chinese in a genome\u2010wide association 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