Several recent genome-wide association studies (GWAS) identified susceptibility loci/genes for Behçet's disease (BD). However, no study has specifically investigated the genetic susceptibility loci associated with intestinal involvement in BD. We aimed to identify distinctive genetic susceptibility loci/genes associated with intestinal involvement in BD and determine their roles in intestinal inflammation as well as their interactions with genes involved in inflammatory bowel disease (IBD). GWAS and validation studies showed intestinal BD-specific associations with an NAALADL2 gene locus (rs3914501, P = 3.8 × 10-4) and a YIPF7 gene locus (rs6838327, P = 3.5 × 10-4). Validation, haplotype, and pathway analyses showed distinct genetic architectures between intestinal BD and BD without intestinal involvement. Furthermore, network analysis revealed shared pathogenic pathways between intestinal BD and IBD. Gene functional analyses indicated that down-regulation of NAALADL2 and YIPF7 expression was associated with exacerbating intestinal inflammatory responses both in vitro and in vivo. Our results provide new insights into intestinal BD-specific genetic variations, which represents a distinct pathway from BD without intestinal involvement. Functional consequences of the intestinal BD-specific NAALADL2 and YIPF7 expression patterns proved a suggestive association with intestinal inflammation risk, which warrants further validation.
Bibliographical noteFunding Information:
This study was supported in part by the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Ministry of Health and Welfare, Republic of Korea (Grant Number A111428, HI13C1345, HI12C0130), the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF- 2014R1A1A1008096), and by the "Kiturami" Faculty Research Assistance Program of Yonsei University College of Medicine for 2012 (6-2012-0135). This study was also supported by the Brain Korea 21 Project for Medical Science, Yonsei University, and biospecimens and data were provided by the Korean Genome Analysis Project (4845-301), the Korean Genome and Epidemiology (4845-302), and Korea Biobank Project (4851-307, KBP-2014-000) that were supported by the Korea Centers for Disease Control & Prevention, Republic of Korea.
All Science Journal Classification (ASJC) codes