Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behçet's disease susceptibility
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Behçet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes. The Epiregulin (EREG), Amphiregulin (AREG), and Neuregulin-1 (NRG1) genes of this pathway stand out as they are also among the top differentially expressed genes. Twelve haplotype tagging SNPs at the EREG-AREG locus and 15 SNPs in NRG1 found associated in at least one published BD genome-wide association study were tested for association with BD in a dataset of 976 Iranian patients and 839 controls. We found a novel association with BD for the rs6845297 SNP located downstream of EREG, and replicated three associations at NRG1 (rs4489285, rs383632, and rs1462891). Multifactor dimensionality reduction analysis indicated the existence of epistatic interactions between EREG and NRG1 variants. EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate BD susceptibility through main effects and gene–gene interactions. These association findings support a role for the EGF/ErbB signaling pathway in BD pathogenesis that warrants further investigation and highlight the importance of combining genetic and genomic approaches to dissect the genetic architecture of complex diseases.
KeywordsGenetics Microarray Association study Behçet's disease Genetic epidemiology
We thank Drs. Ahmet Gul, Elaine F. Remmers, Shigeaki Ohno, Nobuhisa Mizuki and Akira Meguro for sharing their GWAS data. We thank to Dr. Majid Zeidi (Iranian Blood Transfusion Organization) for his excellent support. We are thankful to Doctor Sirous Zeinali (Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran) and Doctor Kayvan Saeedfar for their valuable help. We are also deeply grateful to all study participants and to the genotyping unit at the Instituto Gulbenkian de Ciência.
This research was supported by the Research Committee of the Tehran University of Medical Sciences (grant 132/714), the Portuguese Fundação para a Ciência e a Tecnologia (grant PTDC/SAU-GMG/098937/2008, doctoral fellowship SFRH/BD/43895/2008 to JMX, and a Ciência contract to SAO), and the Portuguese Instituto do Emprego e Formação Profissional (fellowship to JMX, TK, BVF).
Disclosure of potential conflict of interest
There is no conflict of interest to disclose.
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