Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis.
OBJECTIVES: The heritability of RA has been estimated to be approximately 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 th...
| Autors principals: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Idioma: | English |
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2008
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| _version_ | 1826290577819303936 |
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| author | Harney, S Vilariño-Güell, C Adamopoulos, I Sims, A Lawrence, R Cardon, L Newton, J Meisel, C Pointon, J Darke, C Athanasou, N Wordsworth, B Brown, M |
| author_facet | Harney, S Vilariño-Güell, C Adamopoulos, I Sims, A Lawrence, R Cardon, L Newton, J Meisel, C Pointon, J Darke, C Athanasou, N Wordsworth, B Brown, M |
| author_sort | Harney, S |
| collection | OXFORD |
| description | OBJECTIVES: The heritability of RA has been estimated to be approximately 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, CSNK2beta and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta(2)-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. |
| first_indexed | 2024-03-07T02:46:19Z |
| format | Journal article |
| id | oxford-uuid:ac3016ce-3589-43e5-b3fd-0cdb542a6029 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:46:19Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:ac3016ce-3589-43e5-b3fd-0cdb542a60292022-03-27T03:27:03ZFine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ac3016ce-3589-43e5-b3fd-0cdb542a6029EnglishSymplectic Elements at Oxford2008Harney, SVilariño-Güell, CAdamopoulos, ISims, ALawrence, RCardon, LNewton, JMeisel, CPointon, JDarke, CAthanasou, NWordsworth, BBrown, M OBJECTIVES: The heritability of RA has been estimated to be approximately 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, CSNK2beta and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta(2)-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. |
| spellingShingle | Harney, S Vilariño-Güell, C Adamopoulos, I Sims, A Lawrence, R Cardon, L Newton, J Meisel, C Pointon, J Darke, C Athanasou, N Wordsworth, B Brown, M Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. |
| title | Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. |
| title_full | Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. |
| title_fullStr | Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. |
| title_full_unstemmed | Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. |
| title_short | Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis. |
| title_sort | fine mapping of the mhc class iii region demonstrates association of aif1 and rheumatoid arthritis |
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