An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity

Dominik Aschenbrenner (), Isar Nassiri, Suresh Venkateswaran, Sumeet Pandey, Matthew Page, Lauren Drowley, Martin Armstrong, Subra Kugathasan, Benjamin Fairfax and Holm H. Uhlig ()
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Dominik Aschenbrenner: University of Oxford
Isar Nassiri: University of Oxford
Suresh Venkateswaran: Emory University
Sumeet Pandey: University of Oxford
Matthew Page: UCB Pharma
Lauren Drowley: UCB Pharma
Martin Armstrong: UCB Pharma
Subra Kugathasan: Emory University
Benjamin Fairfax: University of Oxford
Holm H. Uhlig: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn’s disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn’s disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn’s disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease.

Date: 2024
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DOI: 10.1038/s41467-024-47218-3

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