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

UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium

Research output

18 Citations (Scopus)

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
DOIs
Publication statusPublished - 1 Mar 2018

Fingerprint

Inflammatory Bowel Diseases
Reactive Oxygen Species
Organoids
Exome
Penetrance
Missense Mutation
Microvilli
Ulcerative Colitis
Single Nucleotide Polymorphism
Oxidoreductases
Epithelium
Genome
Pediatrics
Cell Line
Mutation

Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium (2018). NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunology, 11(2), 562-574. https://doi.org/10.1038/mi.2017.74
UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium. / NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. In: Mucosal Immunology. 2018 ; Vol. 11, No. 2. pp. 562-574.
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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.",
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UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium 2018, 'NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease', Mucosal Immunology, vol. 11, no. 2, pp. 562-574. https://doi.org/10.1038/mi.2017.74

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. / UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium.

In: Mucosal Immunology, Vol. 11, No. 2, 01.03.2018, p. 562-574.

Research output

TY - JOUR

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AU - UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium

AU - Schwerd, T.

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AU - Pandey, S.

AU - Capitani, M.

AU - Meran, L.

AU - Cazier, J. B.

AU - Jung, J.

AU - Mondal, K.

AU - Parkes, M.

AU - Mathew, C. G.

AU - Fiedler, K.

AU - McCarthy, D. J.

AU - Sullivan, P. B.

AU - Rodrigues, A.

AU - Travis, S. P.L.

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AU - Sambrook, J.

AU - Ouwehand, W. H.

AU - Roberts, D. J.

AU - Danesh, J.

AU - Russell, R. K.

AU - Wilson, D. C.

AU - Kelsen, J. R.

AU - Cornall, R.

AU - Denson, L. A.

AU - Kugathasan, S.

AU - Knaus, U. G.

AU - Serra, E. G.

AU - Anderson, C. A.

AU - Duerr, R. H.

AU - McGovern, D. P.B.

AU - Cho, J.

AU - Powrie, F.

AU - Muise, A. M.

AU - Uhlig, H. H.

AU - Donnelly, P.

AU - Bell, J.

AU - Bentley, D.

AU - McVean, G.

AU - Ratcliffe, P.

AU - Taylor, J.

AU - Wilkie, A. O.M.

AU - Donnelly, P.

AU - Broxholme, J.

AU - Buck, D.

AU - Cazier, J. B.

AU - Cornall, R.

AU - Gregory, L.

AU - Gregory, J.

AU - Kanapin, A.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

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UK IBD Genetics Consortium and COLORS in IBD and Oxford IBD cohort study investigators and WGS500 Consortium. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunology. 2018 Mar 1;11(2):562-574. https://doi.org/10.1038/mi.2017.74