title: Angiogenesis-related gene expression analysis in celiac disease.
abstract: Celiac disease (CD) involves disturbance of the small-bowel mucosal vascular network, and transglutaminase autoantibodies (TGA) have been related to angiogenesis disturbance, a complex phenomenon probably also influenced by common genetic variants in angiogenesis-related genes. A set of genes with "angiogenesis" GO term identified in a previous expression microarray experiment (SCG2, STAB1, TGFA, ANG, ERBB2, GNA13, PML, CASP8, ECGF1, JAG1, HIF1A, TNFSF13 and TGM2) was selected for genetic and functional studies. SNPs that showed a trend for association with CD in the first GWAS were genotyped in 555 patients and 541 controls. Gene expression of all genes was quantified in 15 pairs of intestinal biopsies (diagnosis vs. GFD) and in three-dimensional HUVEC and T84 cell cultures incubated with TGA-positive and negative serum. A regulatory SNP in TNFSF13 (rs11552708) is associated with CD (p = 0.01, OR = 0.7). Expression changes in biopsies pointed to TGM2 and PML as up-regulated antiangiogenic genes and to GNA13, TGFA, ERBB2 and SCG2 as down-regulated proangiogenic factors in CD. TGA seem to enhance TGM2 expression in both cell models, but PML expression was induced only in T84 enterocytes while GNA13 and ERBB2 were repressed in HUVEC endothelial cells, with several genes showing discordant effects in each model, highlighting the complexity of gene interactions in the pathogenesis of CD. Finally, cell culture models are useful tools to help dissect complex responses observed in human explants.
authors.affiliation: Immunogenetics Research Laboratory, Endocrinology, Diabetes and Nutrition Research Group, Hospital de Cruces, Barakaldo, Basque Country.
authors.forename: Ainara
authors.initials: A
authors.lastname: Castellanos-Rubio
authors.forename: Sergio
authors.initials: S
authors.lastname: Caja
authors.forename: Iñaki
authors.initials: I
authors.lastname: Irastorza
authors.forename: Nora
authors.initials: N
authors.lastname: Fernandez-Jimenez
authors.forename: Leticia
authors.initials: L
authors.lastname: Plaza-Izurieta
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Vitoria
authors.forename: Markku
authors.initials: M
authors.lastname: Maki
authors.forename: Katri
authors.initials: K
authors.lastname: Lindfors
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Bilbao
mesh_terms: D001706:Biopsy; D002446:Celiac Disease / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D015233:Models, Statistical; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide