RT Journal Article
SR Electronic
T1 XIAP variants in male Crohn's disease
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 66
OP 76
DO 10.1136/gutjnl-2013-306520
VO 64
IS 1
A1 Yvonne Zeissig
A1 Britt-Sabina Petersen
A1 Snezana Milutinovic
A1 Esther Bosse
A1 Gabriele Mayr
A1 Kenneth Peuker
A1 Jelka Hartwig
A1 Andreas Keller
A1 Martina Kohl
A1 Martin W Laass
A1 Susanne Billmann-Born
A1 Heide Brandau
A1 Alfred C Feller
A1 Christoph Röcken
A1 Martin Schrappe
A1 Philip Rosenstiel
A1 John C Reed
A1 Stefan Schreiber
A1 Andre Franke
A1 Sebastian Zeissig
YR 2015
UL http://gut.bmj.com/content/64/1/66.abstract
AB Objective The genetic basis of inflammatory bowel disease (IBD) is incompletely understood. The aim of this study was to identify rare genetic variants involved in the pathogenesis of IBD. Design Exome sequencing and immunological profiling were performed in a patient with early onset Crohn's disease (CD). The coding region of the gene encoding X-linked inhibitor of apoptosis protein (XIAP) was sequenced in samples of 275 paediatric IBD and 1047 adult-onset CD patients. XIAP genotyping was performed in samples of 2680 IBD patients and 2864 healthy controls. Functional effects of the variants identified were investigated in primary cells and cultured cell lines. Results Our results demonstrate the frequent occurrence of private variants in XIAP in about four percent of male patients with paediatric-onset CD. While XIAP mutations are known to be associated with the primary immunodeficiency (PID) X-linked lymphoproliferative disease type 2 (XLP2), CD patients described here exhibited intestinal inflammation in the absence of XLP2 and harboured a spectrum of mutations partially distinct from that observed in XLP2. The majority of XIAP variants identified was associated with a selective defect in NOD1/2 signalling, impaired NOD1/2-mediated activation of NF-κB, and altered NF-κB-dependent cytokine production. Conclusions This study reveals the unanticipated, frequent occurrence of XIAP variants in male paediatric-onset CD. The link between XIAP and NOD1/2, and the association of XIAP variants with XLP2, support the concept of PID in a subset of IBD patients. Moreover, these studies provide a rationale for the implementation of XIAP sequencing in clinical diagnostics in male patients with severe CD.