Identification of genetic susceptibility loci for intestinal Behçet’s disease

Abstract

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.

Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling

“…Four-µm-thick paraffin sections of the distal colon of each animal or of cells were stained with PAS stain or Alcian blue, respectively, according to standard procedures to evaluate the histopathology and goblet cells. Immunohistochemistry was performed using anti-mouse MTNR1A (1:500; Abcam, Cambridge, MA, USA), as previously described 58,63 . After incubation with anti-mouse Reg3β (1:200, R&D Systems, Minneapolis, MN, USA), sections were incubated with Alexa Fluor-488-conjugated secondary antibodies (Thermo Fisher Scientific, San Jose, CA, USA) for immunofluorescence stains.…”

Proteomics-based functional studies reveal that galectin-3 plays a protective role in the pathogenesis of intestinal Behçet’s disease

“…Similar to IBD, intestinal BD is known to have a wax-and-wane disease course and frequent relapse, even with surgery 5 ; however, data regarding disease pathogenesis are extremely limited. Because we recently reported that genetic variants in IL17A , IL23R , STAT4, NAALADL2 , and YIPF7 are associated with intestinal BD pathogenesis 12,13 , in this study, we aimed to investigate differentially expressed proteins of intestinal BD using a proteomics approach.…”

“…In general, intestinal BD has similar clinical and therapeutic characteristics to IBD. However, although we recently identified several genetic loci ( IL17A , IL23R , STAT4, NAALADL2 , and YIPF7 ) associated with susceptibility to intestinal BD 12,13 , relatively little is known about the disease pathogenesis of intestinal BD, highlighting the need for further study to aid in the diagnosis and treatment of this disease.…”

Association of single nucleotide polymorphisms rs7164665, rs71461059, rs74765750, rs6762529 with sudden cardiac death

“…Показано, что в пределах гена находится точка разрыва для транслокации, ассоциированной с развитием синдрома Корнелии де Ланге -редкого синдрома нарушения развития [8]. Редкий аллель полиморфизма rs3914501 гена связан с развитием синдрома Корнелии де Ланге и болезни Кавасаки [9]. С болезнью Кавасаки также связан однонуклеотидный полиморфизм rs17531088 гена NAALADL2 [10].…”

“…Интересно, что в состав фенотипических характеристик синдрома Корнелии де Ланге входят и пороки сердца (дефекты перегородок, стеноз легочной артерии, коарктация аорты) [11]. Тогда как синдром (болезнь) Кавасаки представляет собой системный васкулит новорожденных и детей [9]. Кроме того, однонуклеотидный полиморфизм rs3914501 гена NAALADL2 по данным GWAS ассоциирован с поражением кишечника при болезни Бехчета.…”