Drs. Hou, Z. Yang, and Du contributed equally to this work.
Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome-wide association study
Article first published online: 28 NOV 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 12, pages 4104–4113, December 2012
How to Cite
Hou, S., Yang, Z., Du, L., Jiang, Z., Shu, Q., Chen, Y., Li, F., Zhou, Q., Ohno, S., Chen, R., Kijlstra, A., Rosenbaum, J. T. and Yang, P. (2012), Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome-wide association study. Arthritis & Rheumatism, 64: 4104–4113. doi: 10.1002/art.37708
- Issue published online: 28 NOV 2012
- Article first published online: 28 NOV 2012
- Accepted manuscript online: 22 SEP 2012 11:21AM EST
- Manuscript Accepted: 11 SEP 2012
- Manuscript Received: 29 MAR 2012
- Natural Science Foundation Major International (Regional) Joint Research Project. Grant Number: 30910103912
- National Natural Science Foundation Project. Grant Numbers: 81070722, 81070723, 81270990
- Program for the Training of a Hundred Outstanding Science and Technology Leaders of Chongqing Municipality
- Chongqing Key Laboratory of Ophthalmology (CSTC). Grant Number: 2008CA5003
- Key Project of the Natural Science Foundation. Grant Number: 81130019
- Chongqing Natural Science Foundation (CSTC). Grant Number: 2010BB5389
- Research Fund for the Doctoral Program of Higher Education of China. Grant Number: 20115503110002
- Fund for PAR-EU Scholars Program
To identify susceptibility loci for Behçet's disease (BD) and elucidate their functional role.
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.
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.
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.