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Meta-Analysis
. 2019 Oct 9;14(10):e0223246.
doi: 10.1371/journal.pone.0223246. eCollection 2019.

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

Matthew Traylor  1   2 , Rachel Knevel  3   4   5 , Jing Cui  6 , John Taylor  7 , Westra Harm-Jan  3   4 , Philip G Conaghan  8   9 , Andrew P Cope  10 , Charles Curtis  11   12 , Paul Emery  8   9 , Stephen Newhouse  11   13   14 , Hamel Patel  11 , Sophia Steer  15 , Peter Gregersen  16 , Nancy A Shadick  6 , Michael E Weinblatt  6 , Annette Van Der Helm-van Mil  5 , Jennifer H Barrett  9   17 , Ann W Morgan  8   9 , Cathryn M Lewis  2   12 , Ian C Scott  18   19
Affiliations
Meta-Analysis

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

Matthew Traylor et al. PLoS One. .

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.

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Conflict of interest statement

NAS has received less than $10,000 consultancies from Bristol myers squibb, and research grants from Mallinchrodt Pharmaceuticals and BWH (which is sponsored by Amgen, BMS, Sanofi/Regeneron, Dxterit, Crescendo and UCB). MEW has received less than $10,000 consultancies from Abbvie, Amgen, Novartis, Roche, Glaxo Smith Kline, Merck, Samsung, Crescendo Bioscience, Gilead, Pfizer and UCB, and over $10,000 from Lilly, and BMS. The BRASS study receives funding from Bristol myers squibb, Sanofi/Regeneron, AMGEN, and Crescendo Biosciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Regional association plot for region surrounding rs112112734 showing evidence of significance at P<5x10-8 in the primary trans-ethnic meta-analysis.
Fig 2
Fig 2. Manhattan plots for radiological damage.
Panel A = trans-ethnic primary analysis; Panel B = European primary analysis; Panel C = trans-ethnic secondary analysis; Panel D = European secondary analysis; primary analysis includes age, disease duration and genotypes as explanatory variables; secondary analysis also includes RF as an explanatory variable.
See this image and copyright information in PMC

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