Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome-wide association study.

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 (single-nucleotide polymorphisms [SNPs] rs7574070, rs7572482, and rs897200; P = 3.36 × 10(-7) to 6.20 × 10(-9) ). Increased expression of duanyu18134 was observed in individuals carrying the rs897200 risk genotype AA. Consistent with the idea that duanyu18134 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 duanyu18134 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 duanyu18134 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 duanyu18134 is a novel locus underlying BD. We propose a model in which up-regulation of duanyu18134 expression and subsequent production of inflammatory cytokines, such as IL-17, constitute a potential pathway leading to BD.

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