Traylor, M, Knevel, R, Cui, J, Taylor, J, Harm-Jan, W, Conaghan, PG, Cope, AP, Curtis, C, Emery, P, Newhouse, S, Patel, H, Steer, S, Gregersen, P, Shadick, NA, Weinblatt, ME, Van Der Helm-van Mil, A, Barrett, JH, Morgan, AW, Lewis, CM and Scott, IC (2019) Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases. PLoS One, 14 (10). e0223246 - e0223246.

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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.

Item Type: Article
Uncontrolled Keywords: metaanalysis; genome-wide associations; rheumatoid arthritis; europe; brass; molecular genetics; health services research; genetics of disease
Subjects: R Medicine > R Medicine (General)
R Medicine > RA Public aspects of medicine
Divisions: Faculty of Medicine and Health Sciences > School of Primary, Community and Social Care
Depositing User: Symplectic
Date Deposited: 10 Oct 2019 15:01
Last Modified: 11 Oct 2019 13:33
URI: http://eprints.keele.ac.uk/id/eprint/7011

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