Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Scand J Immunol. 2013 Nov;78(5):447-54. doi: 10.1111/sji.12101.
Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-κB in primary SS. NF-κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB and of IKBKE (IKKε), which is an NF-κB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n = 868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P = 3.4 × 10(-5) , OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and P = 1.3 × 10(-3) , OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P = 5.7 × 10(-3) , OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.
原发性干燥综合征（SS）是一种系统性自身免疫性炎症疾病，其特征在于泪腺和唾液腺中有局灶性淋巴细胞浸润和针对 SSA/Ro 和 SSB/La 抗原的自身抗体。实验研究表明，原发性 SS 中存在 NF-κB 的激活。NF-κB 的激活导致炎症和自身免疫，并且受到抑制和激活蛋白的调节。遗传研究表明，多种自身免疫性疾病与 TNFAIP3（A20）和 TNIP1（ABIN1）之间存在关联，这两种蛋白均为 NF-κB 的抑制剂和 IKBKE（IKKε）的抑制剂，后者是 NF-κB 的激活剂。本研究旨在分析 IKBKE、NFKB1、TNIP1 和 TNFAIP3 基因中的单核苷酸多态性（SNPs）与原发性 SS 的相关性。对来自斯堪的纳维亚（瑞典和挪威，n=684）和英国（n=421）的 1105 例患者和 4460 例对照者（斯堪的纳维亚，n=1662，英国，n=2798）共 12 个 SNP 进行了基因分型。当按存在抗 SSA 和/或抗 SSB 抗体对患者进行分层（n=868）时，病例对照荟萃分析发现，抗体阳性原发性 SS 与 TNIP1 中的两个 SNP 之间存在关联（P=3.4×10(-5)，OR=1.33，95%CI：1.16-1.52 用于 rs3792783 和 P=1.3×10(-3)，OR=1.21，95%CI：1.08-1.36 用于 rs7708392）。TNIP1 风险单倍型与抗体阳性原发性 SS 相关（P=5.7×10(-3)，OR=1.47，95%CI：1.12-1.92）。在斯堪的纳维亚和英国队列的荟萃分析中，与 IKBKE、NFKB1 或 TNFAIP3 均无显著关联。我们的结论是，TNIP1 中的多态性与抗体阳性原发性 SS 相关。
