TY - JOUR
T1 - Genetic associations with radiological damage in rheumatoid arthritis
T2 - Meta-analysis of seven genome-wide association studies of 2,775 cases
AU - Traylor, Matthew
AU - Knevel, Rachel
AU - Cui, Jing
AU - Taylor, John
AU - Harm-Jan, Westra
AU - Conaghan, Philip G.
AU - Cope, Andrew P.
AU - Curtis, Charles
AU - Emery, Paul
AU - Newhouse, Stephen
AU - Patel, Hamel
AU - Steer, Sophia
AU - Gregersen, Peter
AU - Shadick, Nancy A.
AU - Weinblatt, Michael E.
AU - van der Helm-Van Mil, Annette
AU - Barrett, Jennifer H.
AU - Morgan, Ann W.
AU - Lewis, Cathryn M.
AU - Scott, Ian C.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073053900&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0223246
DO - 10.1371/journal.pone.0223246
M3 - Article
C2 - 31596875
AN - SCOPUS:85073053900
SN - 1932-6203
VL - 14
JO - PLoS ONE
JF - PLoS ONE
IS - 10
M1 - e0223246
ER -