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

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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

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, Thomson1,

Anne Hinks1, Bowes1, Gibbons1, Darren Plant1, G.

2, Ioanna Marinou2, Ann W. 3, Emery3, BIRAC

consortium*, Sophia Steer4, Lynne J. Hocking5, M. Reid5,

Wordsworth6, Pille on6, 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

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.

http://rheumatology.oxfordjournals.org/cgi/content/abstract/48/11/1369?etoc

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