A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression
A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression
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DOI：
10.1038/sj.gene.6364375
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发表时间：
2007-04-01
影响因子：
5
通讯作者：
Tomer, Y.
中科院分区：
文献类型：
--
作者：
Jacobson, E. M.;Huber, A. K.;Tomer, Y.
以前，我们和其他人已经证明了CD 40的Kozak序列中的C/T单核苷酸多态性（SNP）与Graves病（GD）的相关性。在这里，使用扩展的患者数据集，我们证实了CD 40 SNP与GD的关联（n = 210，P = 0.002，比值比（OR）= 1.8）。对治疗后甲状腺过氧化物酶（TPO）和/或甲状腺球蛋白（Tg）抗体（Abs）持续升高的患者进行亚组分析（n 126），发现SNP与疾病的相关性显著强于甲状腺抗体阴性的GD患者（P = 5.2 x 10（-5），OR = 2.5）。然而，在健康个体中，CD 40 SNP与TPO/Tg抗体无关。接下来，我们测试了CD 40 SNP与重症肌无力（MG）的相关性，MG和GD一样是一种抗体介导的自身免疫性疾病。对81名MG患者的分析发现SNP与疾病无关。功能研究显示，CD 40 mRNA和蛋白在甲状腺（GD中的靶组织）中有显著表达，但在骨骼肌（MG中的靶组织）中无显著表达。结合，我们的遗传和组织表达数据表明，CD 40 Kozak SNP是特异性的甲状腺抗体的产生参与GD的病因。由SNP驱动的CD 40的甲状腺表达增加可能有助于这种疾病的特异性。
Previously, we and others have demonstrated the association of a C/T single nucleotide polymorphism ( SNP), in the Kozak sequence of CD40, with Graves' disease (GD). Here, using an expanded data set of patients, we confirm the association of the CD40 SNP with GD (n = 210, P = 0.002, odds ratio ( OR) = 1.8). Subset analysis of patients with persistently elevated thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies (Abs), (TPO/Tg Abs), after treatment ( n 126), revealed a significantly stronger association of the SNP with disease ( P = 5.2 x 10(-5), OR = 2.5) than in GD patients who were thyroid antibody-negative. However, the CD40 SNP was not associated with TPO/Tg Abs in healthy individuals. Next, we tested the CD40 SNP for association with Myasthenia Gravis (MG), which, like GD is an antibody-mediated autoimmune condition. Analysis of 81 MG patients found no association of the SNP with disease. Functional studies revealed significant expression of CD40 mRNA and protein in the thyroid ( target tissue in GD) but not in skeletal muscle ( target tissue in MG). Combined, our genetic and tissue expression data suggest that the CD40 Kozak SNP is specific for thyroid antibody production involved in the etiology of GD. Increased thyroidal expression of CD40 driven by the SNP may contribute to this disease specificity.