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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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Matthew Traylor, Rachel Knevel, Jing Cui, John Taylor, Westra Harm-Jan, Philip G. Conaghan, Andrew P. Cope, Charles Curtis, Paul Emery, Stephen Newhouse, Hamel Patel, Sophia Steer, Peter Gregersen, Nancy A. Shadick, Michael E. Weinblatt, Annette van der Helm-Van Mil, Jennifer H. Barrett, Ann W. Morgan, Cathryn M. Lewis, Ian C. Scott

Original languageEnglish
Article numbere0223246
JournalPLoS ONE
Issue number10
Published1 Jan 2019

King's Authors


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 genomewide 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.

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