期刊
PLOS ONE
卷 14, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0223246
关键词
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资金
- Versus Arthritis [19739, 18475, 18387, 20011]
- National Institute for Health Research (NIHR)
- Academy of Medical Sciences
- British Medical Association
- Ann Wilks Memorial Fund
- NIHR University College London Hospitals Biomedical Research Centre
- Farr Institute of Health Informatics Research at UCL Partners
- Medical Research Council (MRC)
- Versus Arthritis
- British Heart Foundation
- Cancer Research UK
- Chief Scientist Office
- Economic and Social Research Council
- Engineering and Physical Sciences Research Council
- NIHR
- National Institute for Social Care and Health Research
- Wellcome Trust [MR/K006584/1]
- MATURA [36661, MR/K015346/1]
- US NIH Pharmacogenomics Research Network (PGRN)
- NIGMS [U19 GM61388]
- RIKEN Center for Integrative Medical Sciences
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- NIHR Biomedical Research Centres at Guy's and St. Thomas' NHS Foundation Trust and King's College London
- South London and Maudsley NHS Foundation Trust and King's College London
- GSTT Charity [TR130505]
- Maudsley Charity [980]
- NIHR infrastructure at Leeds
- MRC [MR/M501633/2, G1001516, G0902393, MR/K015346/1] Funding Source: UKRI
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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