PT  - JOURNAL ARTICLE
AU  - Yvonne Zeissig
AU  - Britt-Sabina Petersen
AU  - Snezana Milutinovic
AU  - Esther Bosse
AU  - Gabriele Mayr
AU  - Kenneth Peuker
AU  - Jelka Hartwig
AU  - Andreas Keller
AU  - Martina Kohl
AU  - Martin W Laass
AU  - Susanne Billmann-Born
AU  - Heide Brandau
AU  - Alfred C Feller
AU  - Christoph Röcken
AU  - Martin Schrappe
AU  - Philip Rosenstiel
AU  - John C Reed
AU  - Stefan Schreiber
AU  - Andre Franke
AU  - Sebastian Zeissig
TI  - XIAP variants in male Crohn's disease
AID  - 10.1136/gutjnl-2013-306520
DP  - 2015 Jan 01
TA  - Gut
PG  - 66--76
VI  - 64
IP  - 1
4099  - http://gut.bmj.com/content/64/1/66.short
4100  - http://gut.bmj.com/content/64/1/66.full
SO  - Gut2015 Jan 01; 64
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.