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


Autoři: Matthew Traylor aff001;  Rachel Knevel aff003;  Jing Cui aff006;  John Taylor aff007;  Westra Harm-Jan aff003;  Philip G. Conaghan aff008;  Andrew P. Cope aff010;  Charles Curtis aff011;  Paul Emery aff008;  Stephen Newhouse aff011;  Hamel Patel aff011;  Sophia Steer aff015;  Peter Gregersen aff016;  Nancy A. Shadick aff006;  Michael E. Weinblatt aff006;  Annette Van Der Helm-van Mil aff005;  Jennifer H. Barrett aff009;  Ann W. Morgan aff008;  Cathryn M. Lewis aff002;  Ian C. Scott aff018
Působiště autorů: Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, Cambridge, United Kingdom aff001;  Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom aff002;  Brigham and Women’s Hospital, Division of Genetics, Raychaudhuri Lab, Boston, MA, United States of America aff003;  Broad institute, Cambridge, MA, United States of America aff004;  Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef, Leiden, the Netherlands aff005;  Division of Rheumatology Immunology and Allergy Brigham & Women's Hospital Harvard Medical School Boston, MA, United States of America aff006;  Leeds Institute of Cancer & Pathology, Worsley Building Level 11 (LIDA), Clarendon Way, Leeds, United Kingdom aff007;  Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom aff008;  NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom aff009;  Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London, London, United Kingdom aff010;  NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, London, United Kingdom aff011;  SGDP Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom aff012;  Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom aff013;  Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, United Kingdom aff014;  Department of Rheumatology, King’s College Hospital, Denmark Hill, London, United Kingdom aff015;  The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, United States of America aff016;  School of Medicine, University of Leeds, Leeds, United Kingdom aff017;  Primary Care Centre Versus Arthritis, Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University, Keele, United Kingdom aff018;  Haywood Academic Rheumatology Centre, Haywood Hospital, Midlands Partnership NHS Foundation Trust, High Lane, Burslem, Staffordshire, United Kingdom aff019
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223246

Souhrn

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.

Klíčová slova:

Brass – Europe – Genetics of disease – Genome-wide association studies – Health services research – Metaanalysis – Molecular genetics – Rheumatoid arthritis


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