DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk
Helmut Grasberger, Andrew T. Magis, Elisa Sheng, Matthew P. Conomos, Min Zhang, Lea S. Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zaatari, Sho Kitamoto, Nobuhiko Kamada, Ryan W. Stidham, Yasutada Akiba, Jonathan Kaunitz, Yael Haberman, Subra Kugathasan, Lee A. Denson, Gilbert S. Omenn, John Y. Kao
Helmut Grasberger, Andrew T. Magis, Elisa Sheng, Matthew P. Conomos, Min Zhang, Lea S. Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zaatari, Sho Kitamoto, Nobuhiko Kamada, Ryan W. Stidham, Yasutada Akiba, Jonathan Kaunitz, Yael Haberman, Subra Kugathasan, Lee A. Denson, Gilbert S. Omenn, John Y. Kao
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Research Article Gastroenterology

DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk

Abstract

A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.

Authors

Helmut Grasberger, Andrew T. Magis, Elisa Sheng, Matthew P. Conomos, Min Zhang, Lea S. Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zaatari, Sho Kitamoto, Nobuhiko Kamada, Ryan W. Stidham, Yasutada Akiba, Jonathan Kaunitz, Yael Haberman, Subra Kugathasan, Lee A. Denson, Gilbert S. Omenn, John Y. Kao

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Figure 7

High impact DUOX2 variants confer increased risk for IBD.

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High impact DUOX2 variants confer increased risk for IBD. (A) Outline of...
(A) Outline of the case-control study comparing the burden of high-impact DUOX2 protein variants in patients with IBD and ancestry-matched non-IBD control cohorts. We stratified variants using population-specific allele frequencies from the gnomAD database. (B) Contribution of individual high impact DUOX2 protein variants to the cumulative allele frequencies. NFE, non–Finnish European; ASJ, Ashkenazi Jewish; FIN, Finnish. Note that the low prevalence of very rare variant carriers in Finnish participants is due to multiple genetic bottlenecks in that isolated population (23). See Supplemental Tables 18–20 for detailed data and Supplemental Figure 6 for the distribution of variants with higher allele frequencies. (C) Carriers of high-impact DUOX2 protein variants are at increased risk for developing IBD. The Forest plot depicts estimated ORs with 95% CI for patients with UC and CD from the 3 ancestry cohorts. The combined OR was calculated using a random-effects model with the Mantel-Haenszel weighting method (Supplemental Table 21). Test of the null hypothesis that OR is equal to 1 (60). (D) Detailed view of DUOX2 variants with predicted complete loss-of-function (i.e., frameshift, stop gained, and splice donor or acceptor site variants) in IBD and control cohorts. Two-tailed Fisher’s exact test. ND, not detected. *P < 0.05; **P < 0.01; ***P < 0.001.