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Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

Prescott, NJ; Lehne, B; Stone, K; Lee, JC; Taylor, K; Knight, J; Papouli, E; Mirza, MM; Simpson, MA; Spain, SL; et al. Prescott, NJ; Lehne, B; Stone, K; Lee, JC; Taylor, K; Knight, J; Papouli, E; Mirza, MM; Simpson, MA; Spain, SL; Lu, G; Fraternali, F; Bumpstead, SJ; Gray, E; Amar, A; Bye, H; Green, P; Chung-Faye, G; Hayee, B; Pollok, R; Satsangi, J; Parkes, M; Barrett, JC; Mansfield, JC; Sanderson, J; Lewis, CM; Weale, ME; Schlitt, T; Mathew, CG; UK IBD Genetics Consortium (2015) Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes. PLoS Genet, 11 (2). e1004955. ISSN 1553-7404 https://doi.org/10.1371/journal.pgen.1004955
SGUL Authors: Pollok, Richard Charles G

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Abstract

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

Item Type: Article
Additional Information: © 2015 Prescott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Correction available at: https://doi.org/10.1371/journal.pgen.1005172
Keywords: Butyrophilins, Colitis, Ulcerative, Crohn Disease, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA Antigens, High-Throughput Nucleotide Sequencing, Humans, Membrane Glycoproteins, Phenotype, Polymorphism, Single Nucleotide, UK IBD Genetics Consortium, Humans, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Membrane Glycoproteins, HLA Antigens, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Developmental Biology, 0604 Genetics
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: PLoS Genet
ISSN: 1553-7404
Language: eng
Dates:
DateEvent
11 February 2015Published
13 December 2014Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
083948/Z/07/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
094491/Z/10/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
G0000934Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
ETM/75Chief Scientist Officehttp://dx.doi.org/10.13039/501100000589
102974Wellcome Trusthttp://dx.doi.org/10.13039/100004440
CZB/4/540Chief Scientist Officehttp://dx.doi.org/10.13039/501100000589
085475/B/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
ETM/137Chief Scientist Officehttp://dx.doi.org/10.13039/501100000589
068545/Z/02Wellcome Trusthttp://dx.doi.org/10.13039/100004440
G0800675Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
085475/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
G0600329Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
NIHR-RP-R3-12-026Department of Healthhttp://dx.doi.org/10.13039/501100000276
ARC1297British Councilhttp://dx.doi.org/10.13039/501100000308
RG100252Royal Societyhttp://dx.doi.org/10.13039/501100000288
PubMed ID: 25671699
Web of Science ID: WOS:000352081800020
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/109415
Publisher's version: https://doi.org/10.1371/journal.pgen.1004955

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