title: Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome-wide association study.
abstract: OBJECTIVE
  To identify susceptibility loci for Behçet's disease (BD) and elucidate their functional role.
  
  
  METHODS
  A genome-wide 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-time polymerase chain reaction, luciferase reporter assay, and enzyme-linked immunosorbent assay were performed.
  
  
  RESULTS
  Our GWAS and replication studies identified a susceptibility locus around STAT4 (single-nucleotide polymorphisms [SNPs] rs7574070, rs7572482, and rs897200; P = 3.36 × 10(-7)  to 6.20 × 10(-9) ). Increased expression of STAT4 was observed in individuals carrying the rs897200 risk genotype AA. Consistent with the idea that STAT4 regulates the production of interleukin-17 (IL-17) and interferon-γ, IL17 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 STAT4 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 STAT4 expression. Additionally, 2 SNPs, rs7574070 and rs7572482, which are tightly linked with rs897200, were cis-expression 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China.
authors.forename: Shengping
authors.initials: S
authors.lastname: Hou
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Liping
authors.initials: L
authors.lastname: Du
authors.forename: Zhengxuan
authors.initials: Z
authors.lastname: Jiang
authors.forename: Qinmeng
authors.initials: Q
authors.lastname: Shu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Fuzhen
authors.initials: F
authors.lastname: Li
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Zhou
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Aize
authors.initials: A
authors.lastname: Kijlstra
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
authors.forename: Peizeng
authors.initials: P
authors.lastname: Yang
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000208:ethnology* / Q000235:genetics*; D001528:Behcet Syndrome / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020381:Interleukin-17; D050797:STAT4 Transcription Factor; D007371:Interferon-gamma