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

Harney, S. M. J., Vilariño-Güell, C., Adamopoulos, I. E., Sims, A. M., Lawrence, R. W., Cardon, L. R., Newton, J. L., Meisel, C., Pointon, J. J., Darke, C., Athanasou, N., Wordsworth, B. P., & Brown, M. A. (2008) Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. Rheumatology, 47(12), pp. 1761-1767.

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Abstract

Objective. 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-DRB10404 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 DRB10404 carrying unrelated RA cases, 125 DRB10404 - carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB104. 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.

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ID Code: 89418
Item Type: Journal Article
Refereed: Yes
Keywords: Immunogenetics, Major histocompatibility complex, Rheumatoid arthritis, allograft inflammatory factor 1, apolipoprotein M, beta 2 microglobulin, casein kinase II, casein kinase II beta, corticosteroid, disease modifying antirheumatic drug, HLA B antigen, HLA DR antigen, hypoxanthine phosphoribosyltransferase, major histocompatibility antigen class 3, methotrexate, protein BAT2, protein bat3, protein BAT4, protein BAT5, tumor necrosis factor antibody, unclassified drug, article, controlled study, gene expression, gene mapping, gene overexpression, genetic association, genotype, haplotype, human, human cell, immunoperoxidase staining, macrophage, major clinical study, osteoarthritis, pathogenesis, peripheral blood mononuclear cell, priority journal, quantitative analysis, reverse transcription polymerase chain reaction, single nucleotide polymorphism, synovium, Arthritis, Rheumatoid, Case-Control Studies, DNA-Binding Proteins, Genetic Predisposition to Disease, HLA-DR Antigens, Humans, Immunoenzyme Techniques, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Reverse Transcriptase Polymerase Chain Reaction, Synovial Membrane
DOI: 10.1093/rheumatology/ken376
ISSN: 1462-0324
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2008 The Authors
Deposited On: 23 Oct 2015 01:10
Last Modified: 22 Aug 2016 02:41

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