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

Author

Listed:
  • Dominik Aschenbrenner

    (University of Oxford
    Novartis Biomedical Research)

  • Isar Nassiri

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Suresh Venkateswaran

    (Emory University)

  • Sumeet Pandey

    (University of Oxford
    GSK Medicines Research Center)

  • Matthew Page

    (UCB Pharma)

  • Lauren Drowley

    (UCB Pharma)

  • Martin Armstrong

    (UCB Pharma)

  • Subra Kugathasan

    (Emory University)

  • Benjamin Fairfax

    (University of Oxford
    University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust
    Oxford University Hospitals NHS Foundation Trust)

  • Holm H. Uhlig

    (University of Oxford
    Oxford University Hospitals NHS Foundation Trust
    University of Oxford)

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.

Suggested Citation

  • Dominik Aschenbrenner & Isar Nassiri & Suresh Venkateswaran & Sumeet Pandey & Matthew Page & Lauren Drowley & Martin Armstrong & Subra Kugathasan & Benjamin Fairfax & Holm H. Uhlig, 2024. "An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47218-3
    DOI: 10.1038/s41467-024-47218-3
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