Genome-wide Association Study Implicates Immune Activation of Multiple Integrin Genes in Inflammatory Bowel Disease

Overview

Journal Nat Genet

Specialty Genetics

Date 2017 Jan 10

PMID 28067908

Citations 637

Authors

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 Tremelling

Ailsa 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

Affiliations

Soon will be listed here.

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.

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