Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases

Abstract

Background

Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants.

Methods

Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases.

Results

In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS.

Conclusions

Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers.

Metadata

Item Type:	Article
Authors/Creators:	Traylor, M Knevel, R Cui, J Taylor, J https://orcid.org/0000-0002-2518-5799 Harm-Jan, W Conaghan, PG https://orcid.org/0000-0002-3478-5665 Cope, AP Curtis, C Emery, P https://orcid.org/0000-0002-7429-8482 Newhouse, S Patel, H Steer, S Gregersen, P Shadick, NA Weinblatt, ME Van Der Helm-van Mil, A Barrett, JH https://orcid.org/0000-0002-1720-7724 Morgan, AW https://orcid.org/0000-0003-1109-624X Lewis, CM Scott, IC
Copyright, Publisher and Additional Information:	© 2019 Traylor 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.
Dates:	Accepted: 17 September 2019 Published (online): 9 October 2019 Published: 9 October 2019
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Musculoskeletal Medicine & Imaging (Leeds)
Funding Information:	Funder Grant number NIHR National Inst Health Research LMBRU 2 MRC R116825 NIHR National Inst Health Research BRC NIHR National Inst Health Research LMBRC Versus Arthritis (formerly ARUK) E0555 Versus Arthritis (formerly ARUK) 18387 Versus Arthritis (formerly ARUK) 18475 NIHR National Inst Health Research NONE GIVEN
Depositing User:	Symplectic Publications
Date Deposited:	20 Sep 2019 09:48
Last Modified:	29 Oct 2019 12:04
Status:	Published
Publisher:	Public Library of Science (PLoS)
Identification Number:	10.1371/journal.pone.0223246
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:151082

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Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases

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