Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis
Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis
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DOI：
10.1093/rheumatology/ken376
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发表时间：
2008-12-01
期刊：
影响因子：
5.5
通讯作者：
Brown, M. A.
中科院分区：
文献类型：
--
作者：
Harney, S. M. J.;Vilarnio-Gueell, C.;Brown, M. A.
目标。 RA的遗传力估计为55，其中MHC约占三分之一。 HLA-DRB1 等位基因与 RA 密切相关，但也可能涉及重要的非 DRB1 MHC 遗传易感因素。此前，我们在紧邻 TNF 着丝粒的 MHC III 类区域的 106 kb 区域中鉴定了两个三标记单倍型，它们与 HLA-DRB10404 单倍型上的 RA 密切相关。在本研究中，我们旨在结合基因分型和基因表达研究来进一步完善这些关联。方法。在 95 个携带 DRB10404 的无关 RA 病例、125 个携带 DRB10404 的健康对照和 87 个父母病例三重 RA 家庭（其中受影响的孩子携带 HLA-DRB104）中，对 39 个核苷酸多态性 (SNP) 进行了基因分型。定量 RTPCR 用于评估 31 例 RA 病例和 21 例种族、年龄组中位置候选 MHC III 类基因 APOM、BAT2、BAT3、BAT4、BAT5、AIF1、C6orf47、CSNK2 和 LY6G5C 以及管家基因、次黄嘌呤鸟嘌呤磷酸核糖转移酶 (HPRT) 和 (2)-微球蛋白 (B2M) 的表达。和性别匹配的健康对照。使用小鼠抗人 AIF1 单克隆抗体，通过间接免疫过氧化物酶技术对 RA、PsA 和 OA 病例的滑膜标本进行染色。结果。在 RA 与单个标记或涉及 AIF1、BAT3 和 CSNK 的两个标记单倍型之间观察到关联。 AIF1 在 RA 单核细胞中也显着过表达（差异为 1.5 至 1.9 倍，与 HPRT 相比，P < 0.02，与 B2M 相比，P < 0.002）。与非炎症性 OA 样本相比，所有炎症性滑膜样本中的滑膜巨噬细胞均清楚地表达 AIF1 蛋白。结论。本文提出的基因分型和表达研究的结果表明 AIF1 在 RA 的病因学和发病机制中发挥作用。
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-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 RTPCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2 and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and (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 mouseanti-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.