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

Lookup NU author(s): Dr Chris LambORCiD, Dr John Mansfield

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2017.

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Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease(1-8), 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.


Publication metadata

Author(s): de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, Kennedy NA, Jostins L, Rice DL, Gutierrez-Achuryl J, Ji SG, Heap G, Nimmo ER, Edwards C, Henderson P, Mowat C, Sanderson J, Satsangi J, Simmons A, Wilson DC, Tremelling M, Hart A, Mathew CG, Newman WG, Parkes M, Lees CW, Uhlig H, Hawkey C, Prescott NJ, Ahmad T, Mansfield JC, Anderson CA, Barrett JC

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2017

Volume: 49

Issue: 2

Pages: 256-261

Print publication date: 01/02/2017

Online publication date: 09/01/2017

Acceptance date: 07/12/2016

Date deposited: 09/01/2019

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ng.3760

DOI: 10.1038/ng.3760


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Funding

Funder referenceFunder name
Addenbrooke's Hospital, Cambridge
NIHR
NIHR Newcastle Biomedical Research Centre
UK Department of Health via NIHR comprehensive Biomedical Research Centre
University of Cambridge
Woolf Fisher Trust scholarship
Crohn's and Colitis UK
Economic and Social Research Council
King's College London
098051Wellcome Trust
093885/Z/10/ZWellcome Trust
094491/Z/10/ZWellcome Trust
MR/J00314X/1Medical Research Council, UK

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