Identification of genetic susceptibility loci for intestinal Behçet disease using a genome-wide association study

Abstract

Several recent genome-wide association studies (GWAS) have identified susceptibility loci/genes for Behcet’s disease (BD). However, no studies have specifically investigated the genetic susceptibility loci associated with intestinal involvement in BD. We evaluated distinctive genetic susceptibility loci/genes associated with intestinal involvement in BD, which can be used to define intestinal BD.

GWAS was performed for 100 Korean BD patients without intestinal involvement, 99 with intestinal involvement, and 557 unaffected individuals. Candidate genes derived from GWAS were then validated using independent cohort samples from 138 patients without intestinal involvement and 196 patients with intestinal involvement. Immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blot, and gene silencing were performed to evaluate functional gene expression in intestinal epithelial cells and in human and murine colon tissues.

GWAS and validation studies showed intestinal BD-specific association with the NAALADL2 gene (rs3914501, OR = 1.914, P = 3.5 × 10-4) and YIPF7 gene locus (rs6838327, OR = 1.567, P = 3.4 × 10-4). Haplotype analysis was suggestive of associations between DCAF12, IL10, NAALADL2, PLCB1, SCHIP1, and TGFBR3 with intestinal BD and its disease phenotype. The results suggest that these genes are potentially causal variants in association with intestinal BD. Gene functional and pathway analyses indicated that intestinal BD shares inflammatory pathways with inflammatory bowel disease (IBD). NAALADL2 and YIPF7 displayed exacerbated inflammatory responses in vitro and in vivo.

In conclusion, our GWAS results separating between intestinal BD and BD without intestinal involvement enable a more comprehensive analysis of disease specificity and provide insight into the common and different pathogenic mechanisms for intestinal BD and IBD