title: Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behçet's disease susceptibility.
abstract: 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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Xavier
authors.forename: Tiago
authors.initials: T
authors.lastname: Krug
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Davatchi
authors.forename: Farhad
authors.initials: F
authors.lastname: Shahram
authors.forename: Benedita V
authors.initials: BV
authors.lastname: Fonseca
authors.forename: Gorete
authors.initials: G
authors.lastname: Jesus
authors.forename: Filipe
authors.initials: F
authors.lastname: Barcelos
authors.forename: Joana
authors.initials: J
authors.lastname: Vedes
authors.forename: Manuel
authors.initials: M
authors.lastname: Salgado
authors.forename: Bahar Sadeghi
authors.initials: BS
authors.lastname: Abdollahi
authors.forename: Abdolhadi
authors.initials: A
authors.lastname: Nadji
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: Moraes-Fontes
authors.forename: Niloofar Mojarad
authors.initials: NM
authors.lastname: Shafiee
authors.forename: Fahmida
authors.initials: F
authors.lastname: Ghaderibarmi
authors.forename: José
authors.initials: J
authors.lastname: Vaz Patto
authors.forename: Jorge
authors.initials: J
authors.lastname: Crespo
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Oliveira
mesh_terms: D000293:Adolescent; D000328:Adult; D066258:Amphiregulin; D001528:Behcet Syndrome / Q000235:genetics* / Q000378:metabolism; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066260:Epiregulin; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C094131:NRG1 protein, human; D020890:Neuregulin-1; D004815:Epidermal Growth Factor