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.

Keywords::

• celiac disease
• angiogenesis
• transglutaminase autoantibodies
• gene expression
• SNP

Acknowledgements

This work was partially funded by Research Project grants from the Spanish Ministry of Science and Innovation (07/0796) and Basque Departments of Health (2006/111030) and Industry (SAIO-2008/00231) to JRB. NF-J and LP-I are predoctoral fellows supported by grants from the Basque Department of Education (BIF-2009-099 and BIF-2010-189, respectively). JRB is co-funded by the I3SNS Program of the Spanish Ministry of Health (CES05/036). This study and the Celiac Disease Study Group have been financially supported by the Academy of Finland, the Sigrid Juselius Foundation, the Foundation for Pediatric Research, the Competitive Research Funding of Tampere University Hospital, the Research Fund of the Finnish Celiac Society and the European Commission IAPP grant TRANSCOM (Contract number PIA-GA-2010-251506).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.