Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Katrina M. de Lange, Loukas Moutsianas, James C. Lee, Christopher A. Lamb, Yang Luo, Nicholas A. Kennedy, Luke Jostins, Daniel L. Rice, Javier Gutierrez-Achury, Sun-Gou Ji, Graham Heap, Elaine R. Nimmo, Cathryn Edwards, Paul Henderson, Craig Mowat, Jeremy Sanderson, Jack Satsangi, Alison Simmons, David C. Wilson, Mark TremellingAilsa Hart, Christopher G. Mathew, William G. Newman, Miles Parkes, Charlie W. Lees, Holm Uhlig, Chris Hawkey, Natalie J. Prescott, Tariq Ahmad, John C. Mansfield, Carl A. Anderson, Jeffrey C. Barrett

    Research output: Contribution to journalLetter

    198 Citations (Scopus)

    Abstract

    Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

    Original languageEnglish
    Pages (from-to)256-261
    Number of pages6
    JournalNature Genetics
    Volume49
    Issue number2
    Early online date9 Jan 2017
    DOIs
    Publication statusPublished - 9 Jan 2017

    Keywords

    • Genome-wide association studies
    • Inflammatory bowel disease

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    de Lange, K. M., Moutsianas, L., Lee, J. C., Lamb, C. A., Luo, Y., Kennedy, N. A., Jostins, L., Rice, D. L., Gutierrez-Achury, J., Ji, S-G., Heap, G., Nimmo, E. R., Edwards, C., Henderson, P., Mowat, C., Sanderson, J., Satsangi, J., Simmons, A., Wilson, D. C., ... Barrett, J. C. (2017). Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nature Genetics, 49(2), 256-261. https://doi.org/10.1038/ng.3760