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

Harney, S. M. J., Vilarino-Guell, C., Adamopoulos, I. E., Sims, Anne-Marie, Lawrence, R. W., Cardon, L. R., Newton, J. L., Meisel, C., pointon, J. J., Darke, C., Athanasou, N., Wordsworth B. P. and Brown, Matthew A. (2008) Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. Rheumatology, 47 12: 1761-1767. doi:10.1093/rheumatology/ken376

Author Harney, S. M. J.
Vilarino-Guell, C.
Adamopoulos, I. E.
Sims, Anne-Marie
Lawrence, R. W.
Cardon, L. R.
Newton, J. L.
Meisel, C.
pointon, J. J.
Darke, C.
Athanasou, N.
Wordsworth B. P.
Brown, Matthew A.
Title Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis
Journal name Rheumatology   Check publisher's open access policy
ISSN 1462-0324
Publication date 2008-12
Year available 2008
Sub-type Article (original research)
DOI 10.1093/rheumatology/ken376
Volume 47
Issue 12
Start page 1761
End page 1767
Total pages 7
Place of publication The United Kingdom
Publisher Oxford University Press
Collection year 2009
Language eng
Subject C1
920116 Skeletal System and Disorders (incl. Arthritis)
110322 Rheumatology and Arthritis
Formatted 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.
Keyword Rheumatoid arthritis
Major histocompatibility complex
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 25 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 26 Mar 2009, 11:51:22 EST by Kylie Hengst on behalf of UQ Diamantina Institute