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Rheumatology Advance Access published online on October 3, 2008
Rheumatology, doi:10.1093/rheumatology/ken376
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis

S. M. J. Harney1, C. Vilariño-Güell1, I. E. Adamopoulos1, A.-M. Sims1,2, R. W. Lawrence3, L. R. Cardon3, J. L. Newton1, C. Meisel1, J. J. Pointon1, C. Darke4, N. Athanasou1, B. P. Wordsworth1 and M. A. Brown1,2

1Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK, 2Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, Brisbane, Australia, 3Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford and 4Welsh Blood Service, Pontyclun, UK.

Correspondence to: M. A. Brown, Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia. E-mail: matt.brown{at}uq.edu.au


  Abstract

Objectives. The heritability of RA has been estimated to be ~55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies.

Methods. Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404-carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT–PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2β and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and β2-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse–anti-human AIF1 monoclonal antibody.

Results. Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples.

Conclusions. The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

KEY WORDS: Rheumatoid arthritis, Immunogenetics, Major histocompatibility complex

Submitted 22 January 2008; revised version accepted 19 August 2008.
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