Journal article

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

T Schwerd, RV Bryant, S Pandey, M Capitani, L Meran, J-B Cazier, J Jung, K Mondal, M Parkes, CG Mathew, K Fiedler, DJ McCarthy, PB Sullivan, A Rodrigues, SPL Travis, C Moore, J Sambrook, WH Ouwehand, DJ Roberts, J Danesh Show all



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 ox..

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University of Melbourne Researchers


Awarded by UK Medical Research Council

Awarded by British Heart Foundation

Awarded by Deutsche Forschungsgemeinschaft

Awarded by Wellcome Trust

Awarded by National Institutes of Health

Awarded by Medical Research Council Hub grant


Awarded by Academy of Medical Sciences (AMS)

Awarded by Medical Research Council

Awarded by Medical Research Foundation

Awarded by National Institute for Health Research

Awarded by The Francis Crick Institute

Awarded by Crohn"s and Colitis UK

Awarded by Alan Turing Institute

Funding Acknowledgements

Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (, which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource (, and the NIHR Cambridge Biomedical Research Centre ( The academic coordinating centre for INTERVAL was supported by core funding from the following: NIHR Blood and Transplant Research Unit in Donor Health and Genomics; UK Medical Research Council (G0800270); British Heart Foundation (SP/09/002); and NIHR Research Cambridge Biomedical Research Centre. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference.<SUP>61</SUP>R.V.B. and H.H.U. were supported by the Medical Research Fund Oxford. Part of this work has formed the MScR thesis of R.V.B. IS. is supported by the Deutsche Forschungsgemeinschaft (SCHW1 730/1-1). H.H.U. and F.P. are supported by the Crohn's & Colitis Foundation of America (CCFA); A M.M., H.H.U., D.P.B.M., and FR by The Leona M. and Harry B. Helmsley Charitable Trust; and H.H.U. by Crohn's and Colitis UK for Crohns -;H.H.U. and D.C.W. by ESPGHAN. S.P. was supported by a Boehringer Ingelheim Foundation grant. F.P. is supported by the Wellcome Trust. U.G.K. is supported by Science Foundation Ireland. The WGS500 Project was funded in part by Illumina. The Oxford IBD cohort is supported by Oxford BRC. L.M. and V.S.W.L. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. S.K. and L.D. are supported by RO1 DK098231. R.K.R. is supported by a NHS Research Scotland Senior Fellowship. D.C.W. is supported by Medical Research Council and Medical Research Foundation for PICTS; Crohn's and Colitis UK. J.R.K. is supported by the National Institutes of Health (K23DK100461 01A1). D.P.B.M. is supported by P01 DK046763 and DK06241 3. This work was funded by a Wellcome Trust Core Award (090532/Z/09/Z) and a Medical Research Council Hub grant (G0900747 91070) to Peter Donnelly, the NIHR Biomedical Research Centre Oxford, the UK Department of Health's NIHR Biomedical Research Centres funding scheme, and Illumina. D.J.M. was supported by the General Sir John Monash Foundation, Australia.