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Rheumatology Advance Access originally published online on September 9, 2009
Rheumatology 2009 48(11):1369-1374; doi:10.1093/rheumatology/kep272
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© The Author(s) 2009. Published by Oxford University Press on behalf of The British Society for Rheumatology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci

Annie McClure1, Mark Lunt1, Steve Eyre1, Xiayi Ke1, Wendy Thomson1, Anne Hinks1, John Bowes1, Laura Gibbons1, Darren Plant1, Anthony G. Wilson2, Ioanna Marinou2, Ann W. Morgan3, Paul Emery3, BIRAC consortium*, Sophia Steer4, Lynne J. Hocking5, David M. Reid5, Paul Wordsworth6, Pille Harrison6, Jane Worthington1 and Anne Barton1

1ARC Epidemiology Unit, The University of Manchester, Manchester, 2School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, 3NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds, 4Clinical and Academic Rheumatology, Kings College Hospital NHS Foundation Trust, London, 5Bone and Musculoskeletal Research Group, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Aberdeen and 6University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Oxford, UK

Correspondence to: Anne Barton, ARC Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK. E-mail: anne.barton{at}manchester.ac.uk.


  Abstract

Objective. Five loci—the shared epitope (SE) of HLA-DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region—have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone.

Methods. We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci.

Results. Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93).

Conclusions. This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.

KEY WORDS: Rheumatoid arthritis, Genetics

*See acknowledgements for a list of the members of the BIRAC Consortium.

Submitted 15 April 2009; revised version accepted 30 July 2009.
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