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

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

© 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