Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome-wide association study
Shengping Hou
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Drs. Hou, Z. Yang, and Du contributed equally to this work.
Search for more papers by this authorZhenglin Yang
Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
Drs. Hou, Z. Yang, and Du contributed equally to this work.
Search for more papers by this authorLiping Du
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Drs. Hou, Z. Yang, and Du contributed equally to this work.
Search for more papers by this authorZhengxuan Jiang
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorQinmeng Shu
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorYuanyuan Chen
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorFuzhen Li
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorQingyun Zhou
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorShigeaki Ohno
Hokkaido University Graduate School of Medicine, Kitaku, Sapporo, Hokkaido, Japan
Search for more papers by this authorAize Kijlstra
University Hospital Maastricht, Maastricht, The Netherlands
Search for more papers by this authorJames T. Rosenbaum
Oregon Health & Science University, Portland
Search for more papers by this authorCorresponding Author
Peizeng Yang
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1, Chongqing 400016, ChinaSearch for more papers by this authorShengping Hou
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Drs. Hou, Z. Yang, and Du contributed equally to this work.
Search for more papers by this authorZhenglin Yang
Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
Drs. Hou, Z. Yang, and Du contributed equally to this work.
Search for more papers by this authorLiping Du
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Drs. Hou, Z. Yang, and Du contributed equally to this work.
Search for more papers by this authorZhengxuan Jiang
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorQinmeng Shu
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorYuanyuan Chen
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorFuzhen Li
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorQingyun Zhou
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
Search for more papers by this authorShigeaki Ohno
Hokkaido University Graduate School of Medicine, Kitaku, Sapporo, Hokkaido, Japan
Search for more papers by this authorAize Kijlstra
University Hospital Maastricht, Maastricht, The Netherlands
Search for more papers by this authorJames T. Rosenbaum
Oregon Health & Science University, Portland
Search for more papers by this authorCorresponding Author
Peizeng Yang
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China
The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1, Chongqing 400016, ChinaSearch for more papers by this authorAbstract
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.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
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| ART_37708_sm_SupplTable1.doc33.5 KB | Supplementary Table 1 |
| ART_37708_sm_SupplTable2.doc37 KB | Supplementary Table 2 |
| ART_37708_sm_SupplFig1.tif2 MB | Supplementary Figure 1 |
| ART_37708_sm_SupplFig2.tif9.5 MB | Supplementary Figure 2 |
| ART_37708_sm_SupplData.doc27.5 KB | Supplementary Data |
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