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Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.

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

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
2
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
3
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne.
4
Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
5
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
6
Precision Medicine Exeter, University of Exeter, Exeter, UK.
7
IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.
8
Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.
9
Christ Church, University of Oxford, St Aldates, UK.
10
Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.
11
Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK.
12
Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.
13
Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children,Edinburgh, UK.
14
Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
15
Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, Department of Gastroenterology, London, UK.
16
Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
17
Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
18
Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.
19
Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK.
20
Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
21
Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK.
22
Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.
23
Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, South Africa.
24
Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.
25
The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
26
Translational Gastroenterology Unit and the Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
27
Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.
28
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
#
Contributed equally

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.

PMID:
28067908
PMCID:
PMC5289481
DOI:
10.1038/ng.3760
[Indexed for MEDLINE]
Free PMC Article

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