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Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease

Genes & Immunity volume 14, pages 447–452 (2013)Cite this article

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Abstract

Genome-wide association studies have implicated common variation at the 20q13 locus in inflammatory bowel disease, particularly for the pediatric Crohn’s form. This locus harbors tumor necrosis factor receptor superfamily (TNFRSF6B), encoding a secreted protein, decoy receptor 3 (DcR3), which binds to and neutralizes pro-inflammatory cytokines of the tumor necrosis factor superfamily. We sought to further the evidence of DcR3’s role in pediatric IBD by identifying missense mutations with functional significance within TNFRSF6B. We sequenced the exons of the gene in 528 Caucasian pediatric IBD cases and 549 Caucasian healthy controls to establish the frequency of such events in each population. Sequencing revealed that our IBD cohort harbored a greater number of missense variants, yielding an odds ratio of 3.9 (P-value=0.005). Using functional assays, we established that the frequency of mutants defective in secretion from cultured cells was greater in the Crohn’s category than in the controls, yielding an odds ratio of 7.1 (P-value=0.004). These results suggest that rare defective variants in TNFRSF6B have a role in the pathogenesis of some cases of IBD and that interventions targeting this group of tumor necrosis factor-family members may benefit patients with IBD.

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Acknowledgements

We thank the patients and control subjects for their invaluable contribution to the study, the University of Pennsylvania DNA Sequencing Facility for excellent technical assistance and the staff at the Center for Applied Genomics for helping with processing the samples, including genotyping and sequencing. This work is supported by an Institutional Development Fund from The Children’s Hospital of Philadelphia and a Research Grant from the Crohn’s and Colitis Foundation of America to HH.

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Authors and Affiliations

  1. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    C J Cardinale, S Panossian, F Wang, C E Kim, F D Mentch, R M Chiavacci, K E Kachelries, R Pandey, S F A Grant & H Hakonarson

  2. Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA

    Z Wei & S F A Grant

  3. Division of Gastroenterology, Hepatology and Nutrition, Philadelphia, PA, USA

    R N Baldassano

  4. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    R N Baldassano & H Hakonarson

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  1. C J Cardinale
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Correspondence to H Hakonarson.

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Author Contributions

Study concept and design by CJC, SFAG, RNB, HH; acquisition of data by CJC, SP, FW, FDM, KK, RNB; technical or material support by CEK, RMC, RP; analysis and interpretation of data by CJC, ZW, SFAG, RNB, HH; drafting of the manuscript by CJC, ZW, SFAG, HH; obtained funding by RNB, HH and study supervision by SFAG, RNB, HH.

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Cardinale, C., Wei, Z., Panossian, S. et al. Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease. Genes Immun 14, 447–452 (2013). https://doi.org/10.1038/gene.2013.43

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