HLA-DR/DQ Haplotype in Rheumatoid Arthritis: Novel Allelic Associations in UK Caucasians

ANITA MILICIC, DOROTHEA LEE, MATTHEW A. BROWN, CHRIS DARKE, and B. PAUL WORDSWORTH

ABSTRACT.

Objective. To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA).

Methods. HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method.

Results. Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRß molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident.

Conclusion. These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region. (J Rheumatol 2002;29:1821-6)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
HLA-DR
HLA-DQ
ASSOCIATION

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From the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; and the Welsh Transplantation and Immunogenetics Laboratory, Welsh Blood Service, Cardiff, UK.

Supported by a grant from the Grenville Bequest for research into genetic susceptibility to rheumatoid arthritis.

A. Milicic, DPhil Student, MSc; D. Lee, BSc, Technician; M.A. Brown, MD, FRACP, Senior Research Fellow, Wellcome Trust Centre for Human Genetics; C. Darke, PhD, Head, Welsh Transplantation and Immunogenetics Laboratory; B.P. Wordsworth, Professor of Rheumatology, Wellcome Centre for Human Genetics.

Address reprint requests to Dr. A. Milicic, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. E-mail: anitam@well.ox.ac.uk

Submitted June 14, 2001; revision accepted March 7, 2002.

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