NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

T Schwerd, R V Bryant, M Capitani, L Meran, J-B Cazier, J Jung, K Mondal, M Parkes, C G Mathew, K Fiedler, D J McCarthy, WGS500 Consortium, Oxford IBD cohort study investigators, COLORS in IBD group investigators, UK IBD Genetics Consortium, P B Sullivan, A Rodrigues, S P L Travis, C. Moore, J SambrookW H Ouwehand, D J Roberts, J Danesh, INTERVAL Study, R K Russell, D C Wilson, J R Kelsen, R Cornall, L A Denson, S Kugathasan, U G Knaus, E G Serra, C A Anderson, R H Duerr, D PB McGovern, J Cho, F Powrie, V. SW Li, A M Muise, H H Uhlig (Lead / Corresponding author), C. Mowat (Contributing member)

    Research output: Contribution to journalArticlepeer-review

    70 Citations (Scopus)
    6 Downloads (Pure)

    Abstract

    Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

    Original languageEnglish
    Pages (from-to)562-574
    Number of pages13
    JournalMucosal Immunology
    Volume11
    Issue number2
    Early online date1 Nov 2017
    DOIs
    Publication statusPublished - Mar 2018

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

    Fingerprint

    Dive into the research topics of 'NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease'. Together they form a unique fingerprint.

    Cite this