epidermal-growth-factor and Behcet-Syndrome

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.

Topics: Adolescent; Adult; Amphiregulin; Behcet Syndrome; EGF Family of Proteins; Epidermal Growth Factor; Epiregulin; Female; Gene Expression Profiling; Genome-Wide Association Study; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Leukocytes, Mononuclear; Male; Middle Aged; Neuregulin-1; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Signal Transduction; Young Adult

Epidermal growth factor (EGF) in saliva is cytoprotective against injuries and contributes to the maintenance of the integrity of the gastrointestinal mucosa. Low salivary EGF levels have been observed in patients with various forms of oral mucosal disease.. Our aim was to determine whether salivary EGF is low in patients with recurrent aphthous stomatitis (RAS) or those with Behçet's disease (BD) when compared with healthy controls.. The study population consisted of 33 BD and 16 RAS patients and 60 healthy controls. Measurement of EGF concentration in human saliva was performed with an enzyme-linked immunosorbent assay using an antibody-coated solid phase.. The mean salivary EGF levels (+/-SD) of active (with oral ulceration) and inactive stages (absence of oral ulceration) of BD (1,939.7 +/- 1,561.5 and 2,305.7 +/- 1,481.6 pg/ml, respectively) and RAS patients (1,650.5 +/- 704.7 and 1,069.9 +/- 539.2 pg/ml, respectively) were both lower than those of the healthy controls (2,758.7 +/- 1,657.9 pg/ml) (p < 0.05 for each).. BD and RAS patients have reduced salivary EGF levels even in the absence of oral ulcerations. EGF could be involved in the pathogenesis of BD and RAS by disturbing the mucosal integrity that may result in a susceptibility to the development of oral ulcers in these diseases.

Topics: Adolescent; Adult; Behcet Syndrome; Colchicine; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Recurrence; Saliva; Stomatitis, Aphthous