Open AccessIdentification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome‐wide association study
Author(s) -
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
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.37708
Subject(s) - expression quantitative trait loci , single nucleotide polymorphism , genome wide association study , stat4 , biology , genotype , snp , allele , genetic association , genetics , locus (genetics) , quantitative trait locus , microbiology and biotechnology , gene , stat , stat3
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. Conclusion 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.