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

Traylor, M.; Knevel, R.; Cui, J.; Taylor, J.; Harm-Jan, W.; Conaghan, P.G.; ... ; Scott, I.C. (2019)

Article / Letter to editor

BackgroundPrevious 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.MethodsSeven 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.ResultsIn 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.ConclusionsOur 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.

• All authors: Traylor, M.; Knevel, R.; Cui, J.; Taylor, J.; Harm-Jan, W.; Conaghan, P.G.; Cope, A.P.; Curtis, C.; Emery, P.; Newhouse, S.; Patel, H.; Steer, S.; Gregersen, P.; Shadick, N.A.; Weinblatt, M.E.; Helm-van Mil, A. van der; Barrett, J.H.; Morgan, A.W.; Lewis, C.M.; Scott, I.C.
• Date: 2019-10-09
• Journal: PLoS ONE
• Volume: 14
• Issue: 10
• DOI: doi:10.1371/journal.pone.0223246