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A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

Abstract

Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67–74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. 70DERAA74, D70 and I67 protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1*0401*0404>*0101*1001 (*0404>*0101: P=0.0003). HLA-DRB1*0401/*0404 compound heterozygosity conferred a risk similar to *0401 homozygosity (P=0.70). Protective effects of D70 and I67 were similar. Predictions of the D70 model fitted the data better than those of the I67 model. The protective effect of D70 showed a gene-dose effect (OR 0.82, 95% CI 0.73–0.92, P=5.8 × 10−4), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15–1.76), P=0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D70 specifically protected against antibody-positive RA.

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Acknowledgements

We thank Henry A. Ehrlich of Roche Molecular Systems, Pleasanton, CA, USA for his collaboration on the HLA-DRB1 typing. We also thank Professor Matthew Brown, University of Queensland, for his helpful comments on an earlier draft of this manuscript.

Funding: The analyses undertaken in this study were funded by the NIHR-Leeds Musculoskeletal Biomedical Research Unit. We would also like to acknowledge Arthritis Research UK (grant refs 17552, E0555 and 18066), Research into Ageing (grant ref 276 to SLM), the Leeds Teaching Hospitals Charitable Trustees, NHS Research and Development Support Fund for Guy's and St Thomas’ and Lewisham NHS Trusts.

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Appendices

Appendix 1

Membership of Yorkshire Early Arthritis Register (YEAR) Consortium

Management Team: Professor Paul Emery1, Professor Philip Conaghan1, Professor Ann Morgan1, Dr Mark Quinn2, Dr Anne-Maree Keenan1, Dr Elizabeth Hensor1

Consultants: Dr Andrew Gough3, Dr Michael Green2,3, Dr Richard Reece4, Dr Lesley Hordon5, Dr Philip Helliwell16, Dr Richard Melsom6, Dr Sheelagh Doherty7, Dr Ade Adebajo8, Dr Andrew Harvey9, Dr Steve Jarrett9, Dr Gareth Huston1, Dr Amanda Isdale2, Dr Mike Martin1, Dr Zunaid Karim9, Professor Dennis McGonagle10, Dr Colin Pease1, Dr Victoria Bejarano1,8

SpRs: Dr Jackie Nam1

Nurses: Claire Brown1, Christine Thomas1, David Pickles1, Alison Hammond1, Beverley Neville3, Alan Fairclough4, Caroline Nunns4, Anne Gill2, Julie Green2, Belinda Rhys-Evans1, Barbara Padwell1, Julie Madden10, Lynda Taylor10, Sally Smith1, Heather King1, Jill Firth6, Jayne Heard7, Linda Sigsworth6

Lab Staff: Diane Corscadden1, Karen Henshaw1, Lubna-Haroon Rashid1, Stephen G Martin1, James I Robinson1

1Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, Leeds, UK 2York District Hospital, York, UK 3Harrogate District Hospital, Harrogate, UK 4Huddersfield Royal Infirmary, Huddersfield, UK 5Dewsbury District and General Hospital, Dewsbury, UK 6St Luke's Hospital, Bradford, UK

7Hull Royal Infirmary, Hull, UK

8Barnsley District General Hospital, Barnsley, UK

9Pinderfields General Hospital, Wakefield, UK

10Calderdale Royal Hospital, Halifax, UK

Appendix 2

Membership of the UK Rheumatoid Arthritis Genetics (UKRAG) Consortium

University of Manchester1: Stephen Eyre, Anne Hinks, Laura J Gibbons, John Bowes, Edward Flynn, Paul Martin, Wendy Thomson, Anne Barton, Jane Worthington.

University of Leeds2: YEAR consortium, Ann W Morgan, Paul Emery

University of Sheffield3: Anthony G. Wilson University of London4: Sophia Steer University of Aberdeen5: Lynne Hocking4 David M Reid University of Oxford6: Pille Harrison, Paul Wordsworth

1arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK

2Leeds Institute of Molecular Medicine, Section of Musculoskeletal Disease, University of Leeds, Leeds LS9 7TF, UK

3School of Medicine & Biomedical Sciences, The University of Sheffield, Sheffield S10 2JF, UK

4Clinical and Academic Rheumatology, Kings College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK

5Bone Research Group, Department of Medicine & Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, UK

6University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Oxford OX3 7LD, UK

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Mackie, S., Taylor, J., Martin, S. et al. A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population. Genes Immun 13, 120–128 (2012). https://doi.org/10.1038/gene.2011.60

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