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.
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-humanAIF1 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.
Authors: Yee Soo Chae; Soo Jung Lee; Joon Ho Moon; Byung Woog Kang; Jong Gwang Kim; Sang Kyun Sohn; Jin Hyang Jung; Ho Yong Park; Ji Young Park; Hye Jung Kim; Sang-Woo Lee Journal: Med Oncol Date: 2010-05-26 Impact factor: 3.064
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Authors: Alexandra Nieters; Lucia Conde; Susan L Slager; Angela Brooks-Wilson; Lindsay Morton; Danica R Skibola; Anne J Novak; Jacques Riby; Stephen M Ansell; Eran Halperin; Tait D Shanafelt; Luz Agana; Alice H Wang; Anneclaire J De Roos; Richard K Severson; Wendy Cozen; John Spinelli; Katja Butterbach; Nikolaus Becker; Silvia de Sanjose; Yolanda Benavente; Pierluigi Cocco; Anthony Staines; Marc Maynadié; Lenka Foretova; Paolo Boffetta; Paul Brennan; Qing Lan; Yawei Zhang; Tongzhang Zheng; Mark Purdue; Bruce Armstrong; Anne Kricker; Claire M Vajdic; Andrew Grulich; Martyn T Smith; Paige M Bracci; Stephen J Chanock; Patricia Hartge; James R Cerhan; Sophia S Wang; Nathaniel Rothman; Christine F Skibola Journal: Blood Date: 2012-10-09 Impact factor: 22.113
Authors: Dorothee Nickles; Hsuan P Chen; Michael M Li; Pouya Khankhanian; Lohith Madireddy; Stacy J Caillier; Adam Santaniello; Bruce A C Cree; Daniel Pelletier; Stephen L Hauser; Jorge R Oksenberg; Sergio E Baranzini Journal: Hum Mol Genet Date: 2013-06-06 Impact factor: 6.150